CN1162957A - Isoxazole Derivatives - Google Patents

Abstract

An isoxazole derivative represented by general formula (I), having an excellent monoamine oxidase inhibitory activity, and being useful as a remedy or preventive for nervous diseases such as Parkinson's diseases, wherein R<1> represents hydrogen, halogen, alkyl, alkoxy, hydroxy, alkylthio, amino, alkanoyl, alkanoylamino, alkanoyloxy, alkoxycarbonyl, carboxy, (alkylthio)-thiocarbonyl, carbamoyl, nitro or cyano; R<2> represents amino; m represents an integer of 1 to 3; n represents an integer of 1 to 6; ring A represents benzene, naphthalene or aromatic heterocycle; and X represents oxygen or sulfur.

Description

Isoxazole Derivatives

[technical field]

The present invention relates to monoamine oxidase inhibitors having B-type and A-type monoamine oxidase activity (particularly having significant B-type monoamine oxidase inhibitory effect) and having therapeutic or preventive effects on neurological diseases including Parkinson's disease, depression and Alzheimer's disease (especially Parkinson's disease) isoxazole derivatives. The present invention also relates to monoamine oxidase inhibitors containing isoxazole derivatives as active ingredients.

[Background technique]

Parkinson's disease is a chronic progressive disorder that causes akinesia, muscle rigidity, and tremors, with consequent degeneration of dopaminergic neurons in the substantia nigra. It has now been found that Parkinson's disease is caused by reduced brain concentrations of dopamine, a neurotransmitter that causes degenerative, vascular and inflammatory changes in the basal ganglia, specifically in the caudate nucleus and putamen. In order to replenish the depleted dopamine in the brain, especially in the striatum, the most effective treatment and the one often used is the administration of levodopa. However, treatment with levodopa alone has many problems due to serious side effects. Recently, many trials have been conducted to treat Parkinson's disease by inhibiting type B monoamine oxidase (a dopamine decomposing enzyme) and preventing the breakdown of dopamine and deprenyl, a monoamine oxidase inhibitor, has been developed.

Now, Japanese Patent Sho 47-6302 discloses benzisoxazole derivatives such as compounds A and B, which generally act on the nervous system and have cardiovascular effects, and can be used as local anesthetics, antihistamines, anti-inflammatory drugs , tonic and antispasmodic.

(Compound A) (Compound B)

In addition, Farmaco, Ed. Sci., 23, 1081(1968)., ibid., 24, 440(1069). It is stated that compound B has anti-inflammatory effect and local (infiltration) anesthetic effect. However, the monoamine oxidase inhibitory activity of the compounds A and B is not known at all. [Content of the invention]

The present inventor has devoted himself to studying the synthesis and pharmacological activity of isoxazole compounds for a long time, with the aim of finding a significant therapeutic agent for Parkinson's disease, and found that isoxazole derivatives with specific structures have strong inhibitory effects on type B and type A monoamine oxidase (especially strong inhibitory effect on B-type monoamine oxidase) and has therapeutic or preventive effects on neurological diseases including Parkinson's disease, depression and Alzheimer's disease (particularly Parkinson's disease), thus completing the present invention.

The present invention provides isoxazole derivatives having significant B-type monoamine oxidase inhibitory activity and A-type monoamine oxidase inhibitory activity, their synthesis method and the monoamine oxidase inhibitor containing the active ingredient of the isoxazole derivatives.

其中R¹表示氢原子；卤原子；C₁-C₆烷基；卤素-或C₁-C₄烷氧基-取代的C₁-C₄烷基；C₁-C₆烷氧基；卤代C₁-C₆烷氧基；羟基；C₁-C₆烷硫基；氨基；单C₁-C₆烷基氨基；二C₁-C₆烷基氨基；C₁-C₆链烷酰基；C₁-C₆链烷酰氨基；C₁-C₆链烷酰氧基；C₁-C₆烷氧羰基；羧基；(C₁-C₆烷硫基)硫代羰基；氨基甲酰基；单C₁-C₆烷基氨基甲酰基；二C₁-C₆烷基氨基甲酰基；硝基或氰基基团，R²表示氨基基团，m表示1-3的整数，n表示1-6的整数，环A表示与异噁唑环稠合的苯环，与异噁唑环稠合的萘环或与异噁唑环稠合的含有1或2个选自氧、氮和硫杂原子的5或6元芳杂环，和X表示氧原子或硫原子，条件是，当m是2或3的整数时，所述各取代基R¹相同或不同。The isoxazole derivatives described in the present invention are compounds of the following general formula (I),

wherein R ¹ represents a hydrogen atom; a halogen atom; C ₁ -C ₆ alkyl; halogen- or C ₁ -C ₄ alkoxy-substituted C ₁ -C ₄ alkyl; C ₁ -C ₆ alkoxy; _Substituted C ₁ -C ₆ alkoxy; Hydroxy; C ₁ -C ₆ Alkylthio; Amino; Mono C ₁ -C ₆ Alkylamino; Di C _{1 -C 6} Alkylamino; Acyl; C ₁ -C ₆ alkanoylamino; C ₁ -C ₆ alkanoyloxy; C ₁ -C ₆ alkoxycarbonyl; carboxyl; (C ₁ -C ₆ alkylthio)thiocarbonyl; aminomethyl Acyl; single C ₁ -C ₆ alkylcarbamoyl; two C ₁ -C ₆ alkylcarbamoyl; nitro or cyano group, R ² represents an amino group, m represents an integer of 1-3, n Represents an integer from 1 to 6, ring A represents a benzene ring fused to an isoxazole ring, a naphthalene ring fused to an isoxazole ring, or a ring fused to an isoxazole ring containing 1 or 2 atoms selected from oxygen and nitrogen and a 5- or 6-membered aromatic heterocycle with a sulfur heteroatom, and X represent an oxygen atom or a sulfur atom, provided that, when m is an integer of 2 or 3, each of the substituents R ¹ is the same or different.

In addition, the active ingredient of the monoamine oxidase inhibitor of the present invention is an isoxazole derivative of the following general formula (II),

wherein R ¹ , m, n, ring A and X are as defined above, and

R ² _a represents amino; mono-C ₁ -C ₄ alkylamino; di-C ₁ -C ₄ alkylamino; or a 5- or 6-membered heterocycle containing 1 nitrogen atom and optionally another nitrogen or oxygen atom (provided that the group in question is attached via said nitrogen atom).

In the general formulas (I) and (II), the "halogen atom" in the definition of ^R above can be fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine or bromine atom, and more preferably fluorine or chlorine atom.

The "C ¹ _{-C 6} alkyl group" mentioned in the definition of R above is a linear or branched chain alkyl group with 1-6 carbon atoms, which can be, for example, methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methyl Pentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethyl butyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl groups, preferably C ₁ -C ₄ alkane group, and more preferably methyl or ethyl. Particularly preferred is methyl.

The "halogen- or C ₁ -C ₄ alkoxy substituted C ₁ -C ₄ alkyl group" mentioned above in the definition of R ¹ is the above mentioned halogen or the following C ₁ -C ₄ alkoxy substituted C ₁ -C ₄ alkyl groups; said halogen-substituted alkyl groups may be, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2 , 2,2-trifluoroethyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl, 4-fluorobutyl or 4-chlorobutyl groups, and the alkoxy-substituted The alkyl group can be methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butyl Oxyethyl, propoxypropyl or butoxybutyl groups, preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2, 2-trifluoroethyl, methoxymethyl or methoxyethyl groups, and more preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2- Trifluoroethyl, methoxymethyl and methoxyethyl groups, while further preferred are trifluoromethyl, 2,2,2-trifluoroethyl or methoxymethyl groups. Particularly preferred is trifluoromethyl.

The "C ₁ -C ₆ alkoxy group" mentioned in the above definition of R ¹ is a group in which the above "C ₁ -C ₆ alkyl group" is bonded to an oxygen atom and they may be methoxy, ethoxy, Oxygen, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyl Oxygen, 1-ethylpropoxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3 -Dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy group, 2,3-dimethylbutoxy or 2-ethylbutoxy, preferably a C ₁ -C ₄ alkoxy group, and more preferably a methoxy or ethoxy group. Particularly preferred is methoxy.

The "halo-C ₁ -C ₆ -alkoxy group" mentioned in the above definition of R ¹ is a group in which the above-mentioned halogen atom is bonded to the above-mentioned C ₁ -C ₆ alkoxy group and they may be fluoromethoxy chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, 1-fluoro Ethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-fluoropropoxy, 3 - bromopropoxy, 4-fluorobutoxy, 5-fluoropentyloxy or 6-iodohexyloxy groups, preferably fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy radical, trifluoromethoxy, trichloromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy or 2,2,2-trifluoroethoxy groups, and More preferred are fluoromethoxy, difluoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy groups. Particularly preferred is difluoromethoxy.

The "C ₁ -C ₆ alkylthio group" mentioned above in the definition of R ¹ is a group in which the above "C ₁ -C ₆ alkyl group" is bonded to a sulfur atom and they may be methylthio, ethyl Thio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio Thio, 1-ethylpropylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3,3 -Dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio group, 2,3-dimethylbutylthio or 2-ethylbutylthio group, preferably C ₁ -C ₄ alkylthio group, and more preferably methylthio or ethylthio group. Particularly preferred is methylthio.

The "single C ₁ -C ₆ alkylamino group" mentioned above in the definition of R ¹ is a group in which the above "C ₁ -C ₆ alkyl group" is bonded to an amino group, and they can be methylamino, ethylamino , propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino or hexylamino groups, preferably mono-C ₁ -C ₄ alkylamino groups, and more preferably methylamino or ethylamino group. Particularly preferred is methylamino.

The "di-C ₁ -C ₆ alkylamino group" mentioned in the definition of R ^above can be, for example, dimethylamino, ethylmethylamino, methylpropylamino, isopropylmethylamino, butylmethylamino , isobutylmethylamino, sec-butylmethylamino, tert-butylmethylamino, diethylamino, ethylpropylamino, ethylisopropylamino, dipropylamino, dibutylamino, dipentylamino or dihexyl Amino groups, preferably di-C ₁ -C ₄ alkylamino groups, and more preferably dimethylamino or diethylamino groups. Particularly preferred is dimethylamino.

The "C ¹ _{-C 6} alkanoyl group" mentioned in the definition of R above is a straight chain or branched chain alkanoyl group with 1 to 6 carbon atoms and may be formyl, acetyl, propionyl, butyryl , isobutyryl, pentanoyl, pivaloyl, valeryl or isovaleryl groups, preferably C ₁ -C ₄ alkanoyl groups, and more preferably formyl or acetyl.

The "C ¹ _{-C 6} alkanoylamino group" mentioned in the definition of R above is a straight chain or branched chain alkanoylamino group with 1 to 6 carbon atoms and may be formamido, acetamido, Propionylamino, butyrylamino, isobutyrylamino, pentanoylamino, pivalylamino, valerylamino or isovalerylamino groups, preferably C ₁ -C ₄ alkanoylamino groups group, and more preferably a formylamino or acetamido group.

The "C ¹ _{-C 6} alkanoyloxy group" mentioned in the definition of R above is a linear or branched chain alkanoyloxy group with 1 to 6 carbon atoms and may be formyloxy, Acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, pivaloyloxy, valeryloxy or isovaleryloxy groups, C ₁ -C ₄ alkanoyloxy groups are preferred, and formyloxy or acetoxy groups are more preferred.

The "C ¹ _{-C 6} alkoxycarbonyl group" mentioned in the definition of R above can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butyl An oxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl or hexyloxycarbonyl group, preferably a C ₁ -C ₄ alkoxycarbonyl group, and more preferably a methoxycarbonyl or ethoxycarbonyl group. Particularly preferred is methoxycarbonyl.

The "(C ₁ -C ₆ alkylthio)thiocarbonyl group" mentioned in the definition of R ^above is a thiocarbonyl group bonded to a linear or branched chain alkylthio group of 1 to 6 carbon atoms and may be (methylthio)thiocarbonyl, (ethylthio)thiocarbonyl, (propylthio)thiocarbonyl, (isopropylthio)thiocarbonyl, (butylthio)thiocarbonyl, ( isobutylthio)thiocarbonyl, (sec-butylthio)thiocarbonyl, (tert-butylthio)thiocarbonyl, (pentylthio)thiocarbonyl or (hexylthio)thiocarbonyl groups, preferably (C ₁ -C ₄ alkylthio)thiocarbonyl group, and more preferably (methylthio)thiocarbonyl or (ethylthio)thiocarbonyl, most preferably (methylthio)thiocarbonyl.

The "single C ₁ -C ₆ alkylcarbamoyl" group mentioned in the definition of R ^above can be methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, Butylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl or hexylcarbamoyl groups, preferably mono-C ₁ -C ₄ alkylamino formyl group, and more preferably methylcarbamoyl or ethylcarbamoyl.

The "di-C ₁ -C ₆ alkylcarbamoyl group" mentioned in the definition of R ^above can be dimethylcarbamoyl, ethylmethylcarbamoyl, diethylcarbamoyl, dipropyl Carbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl, diisobutylcarbamoyl, di-sec-butylcarbamoyl, di-tert-butylcarbamoyl, dipentylcarbamoyl or A dihexylcarbamoyl group, preferably a diC ₁ -C ₄ alkylcarbamoyl group, and more preferably a dimethylcarbamoyl group or a diethylcarbamoyl group. Particularly preferred is dimethylcarbamoyl.

The "5- or 6-membered aromatic heterocycle fused to an isoxazole ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur" mentioned in the definition of ring A above can be, for example, furyl, thienyl, pyrrolyl , imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl rings, preferably furyl, thienyl or pyridyl rings, And more preferably a pyridyl ring.

Also, the above-mentioned isoxazole compound fused with a furyl, thienyl or pyridyl ring is a compound having a structure represented by the following formulas (III) to (XII). Compounds of formula (III), (IV), (IX), (X), (XI) or (XII) are preferred, and more preferred are compounds of formula (IX), (X), (XI) or (XII), optionally preferably a compound of formula (IX) or (XII). Particularly preferred are compounds having the structure represented by formula (XII).

The "mono C ₁ -C ₄ alkylamino group" mentioned above in the _definition of R ² a is as described above for R ¹ and particularly preferably methylamino.

The "di-C ₁ -C ₄ alkylamino group" mentioned above in the _definition of R ² a is as described above for R ¹ and is particularly preferably dimethylamino.

The "5- or 6-membered heterocyclic ring containing 1 nitrogen atom and optionally another nitrogen or oxygen atom (provided that the group is attached via the relevant nitrogen atom)" mentioned in the definition of R ² _a above may be, for example, pyrrole Base, imidazolyl, pyrazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl or morpholinyl groups, preferably piperidinyl or morpholinyl.

If ^R in the compound of formula (I) and (II) of the present invention is a basic group such as amino or alkylamino group, it can be converted into a corresponding pharmaceutically acceptable salt by treating it with an acid according to a conventional method . For example, the compound (1) or (II) is treated with the corresponding acid in a solvent (e.g. ethers, especially dioxane) at room temperature for 5-30 minutes and the precipitated crystals are filtered or reduced Evaporation of the solvent under reduced pressure gave the salt. Such salts may be salts of inorganic acids such as hydrochlorides, hydrobromides, hydroiodides, nitrates, pernitrates, sulfates or phosphates, sulfonates such as methanesulfonate, triflate salts, ethanesulfonates, benzenesulfonates or p-toluenesulfonates, carboxylates such as fumarate, succinate, citrate, tartrate, oxalate and maleate, or amino acids Salts such as glutamate or aspartate.

If R ¹ in compounds (I) and (II) of the present invention is an acidic group such as hydroxyl or carboxyl, it can be converted into a corresponding pharmaceutically acceptable salt by treating with a base in a conventional method. For example, at room temperature, in a solvent (such as ethers, especially diethyl ether or tetrahydrofuran), the compound (I) or (II) is treated with the corresponding base for 5-30 minutes and the precipitated crystals are filtered or reduced The salt of the compound (I) or (II) can be obtained by distilling off the solvent under reduced pressure. Such salts may be alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, or organic amine salts such as guanidine, triethylamine or dicyclohexylamine salts.

The compound (I) or (II) or a salt thereof of the present invention can absorb moisture, absorb water or become a hydrate when left in the air or when recrystallized, and these salts containing water molecules are also included in the scope of the present invention.

The compounds (I) or (II) or salts thereof of the present invention may contain asymmetric carbon atoms in their molecules, and thus, stereoisomers in R- and S-configurations may exist. These single compounds as well as mixtures thereof in any proportion are also included within the scope of the present invention.

The following compounds are preferred compounds of the present invention (I); (1) ^R is hydrogen, halogen, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, fluoromethoxy, chloromethoxy, difluoro Methoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2,2-tri Fluoroethoxy, Hydroxy, C ₁ -C ₄ Alkylthio, Amino, Mono C _{1 -C} 4 Alkylamino, Di C ₁ -C ₄ Alkylamino, Formyl, Acetyl, Formylamino, Acetylamino , C ₁ -C ₄ alkanoyloxy, C ₁ -C ₄ alkoxycarbonyl, carboxyl, (methylthio)thiocarbonyl, (ethylthio)thiocarbonyl, carbamoyl, methylcarbamoyl , ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, nitro or cyano groups. (2) R ¹ is hydrogen, halogen, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methyl Oxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, difluoromethoxy, hydroxyl, C ₁ -C ₄ alkylthio, amino, methylamino, ethylamino, dimethylamino, di Ethylamino, formyl, acetyl, formylamino, acetylamino, C ₁ -C ₄ alkoxycarbonyl, carboxyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, Compounds with diethylcarbamoyl, nitro or cyano groups. (3) ^R1 is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, hydroxyl, methylthio, ethylthio, amino , methylamino, ethylamino, dimethylamino, formyloxy, acetoxy, methoxycarbonyl, ethoxycarbonyl, carboxyl, carbamoyl, nitro or cyano groups. (4) Compounds in which R ¹ is a hydrogen, fluorine, chlorine, bromine, methyl, methoxy, methylthio, difluoromethoxy, methoxycarbonyl, nitro or cyano group. (5) The compound where m is 2. (6) The compound in which m is 1. (7) Compounds in which n is 2-4. (8) Compounds in which n is 2. (9) The ring A is phenyl, naphthyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridyl Compounds with an azinyl, pyrimidinyl or pyridazinyl ring. (10) The compound in which the ring A is a phenyl, naphthyl or pyridyl ring. (11) The compound in which the ring A is a phenyl or pyridyl ring. (12) The compound in which the ring A is a phenyl ring. (13) A compound in which X is oxygen. (14) 3-(2-Aminoethoxy)benzisoxazole,

3-(2-Aminoethylthio)benzisoxazole,

3-(2-Aminoethoxy)-fluorobenzoisoxazole,

3-(2-Aminoethylthio)-fluorobenzisoxazole,

3-(2-Aminoethoxy)-fluoro-methylbenzisoxazole,

3-(2-Aminoethylthio)-fluoro-methylbenzisoxazole,

3-(2-Aminoethoxy)-fluoro-methylthiobenzisoxazole,

3-(2-Aminoethoxy)-fluoro-methoxycarbonylbenzisoxazole,

3-(2-Aminoethoxy)-fluoro-carbamoylbenzisoxazole,

3-(2-Aminoethoxy)-fluoro-cyanobenzisoxazole,

3-(2-Aminoethylthio)-fluoro-cyanobenzisoxazole,

3-(2-Aminoethoxy)-chlorobenzisoxazole,

3-(2-Aminoethylthio)-chlorobenzisoxazole,

3-(2-Aminoethoxy)-dichlorobenzisoxazole,

3-(2-Aminoethylthio)-dichlorobenzisoxazole,

3-(2-Aminoethoxy)-chloro-methylbenzisoxazole,

3-(2-Aminoethylthio)-chloro-methylbenzisoxazole,

3-(2-Aminoethoxy)-chloro-carbamoylbenzisoxazole,

3-(2-Aminoethoxy)-chloro-cyanobenzisoxazole,

3-(2-Aminoethylthio)-chloro-cyanobenzisoxazole,

3-(2-Aminoethoxy)-dichloro-methylbenzisoxazole,

3-(2-Aminoethoxy)-bromobenzisoxazole,

3-(2-Aminoethoxy)-bromo-methylbenzisoxazole,

3-(2-Aminoethoxy)-methylbenzisoxazole,

3-(2-Aminoethylthio)-methylbenzisoxazole,

3-(2-Aminoethoxy)-dimethylbenzisoxazole,

3-(2-Aminoethoxy)-methyl-methoxybenzisoxazole,

3-(2-Aminoethoxy)-methyl-methylthiobenzisoxazole,

3-(2-Aminoethoxy)-methyl-methoxycarbonylbenzisoxazole,

3-(2-Aminoethoxy)-methyl-carbamoylbenzoisoxazole,

3-(2-Aminoethoxy)-methyl-cyanobenzisoxazole,

3-(2-Aminoethoxy)-trifluoromethylbenzisoxazole,

3-(2-Aminoethoxy)-methoxybenzisoxazole,

3-(2-Aminoethylthio)-methoxybenzisoxazole,

3-(2-Aminoethoxy)-difluoromethoxybenzisoxazole,

3-(2-Aminoethoxy)-hydroxybenzoisoxazole,

3-(2-Aminoethoxy)-aminobenzisoxazole,

3-(2-Aminoethylthio)-aminobenzisoxazole,

3-(2-Aminoethoxy)-methylaminobenzisoxazole,

3-(2-Aminoethoxy)-dimethylaminobenzisoxazole,

3-(2-Aminoethoxy)-acetoxybenzisoxazole,

3-(2-Aminoethoxy)-carboxybenzisoxazole,

3-(2-Aminoethoxy)-methoxycarbonylbenzisoxazole,

3-(2-Aminoethoxy)-carbamoylbenzisoxazole,

3-(2-Aminoethoxy)-nitrobenzisoxazole,

3-(2-Aminoethylthio)-nitrobenzisoxazole,

3-(2-Aminoethoxy)-cyanobenzisoxazole,

3-(2-Aminoethoxy)-naphthoisoxazole,

3-(2-Aminoethoxy)-pyridoisoxazole,

3-(2-Aminoethoxy)-chloropyridoisoxazole,

3-(2-Aminoethylthio)-chloropyridisoxazole,

3-(2-Aminoethoxy)-picolineisoxazole, or

3-(2-Aminoethoxy)-trifluoromethylpyridoisoxazole,

Any one of 1-5 combinations selected from groups (1)-(4), (5)-(6), (7)-(8), (9)-(12) and (13) Compounds are also preferred, such as the combinations given below. (15)(1) and (7), (16)(2), (7) and (9), (17)(2), (8) and (10), (18)(3), (8 ) and (10), (19)(3), (5), (8) and (11), (20)(4), (8) and (10), (21)(4), (5) , (8) and (11), (22) (4), (5), (8) and (12).

The following compounds are preferred compounds (II) of the present invention as active ingredients of monoamine oxidase inhibitors; (1) ^R is hydrogen, halogen, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl , 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, fluoromethoxy, Chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2,2-Trifluoroethoxy, Hydroxy, C ₁ -C ₄ Alkylthio, Amino, Mono C ₁ -C ₄ Alkylamino, Di C ₁ -C ₄ Alkylamino, Formyl, Acetyl , formylamino, acetylamino, C ₁ -C ₄ alkanoyloxy, C ₁ -C ₄ alkoxycarbonyl, carboxyl, (methylthio) thiocarbonyl, (ethylthio) thiocarbonyl, aminomethyl acyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, nitro or cyano groups. (2) R ¹ is hydrogen, halogen, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methyl Oxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, difluoromethoxy, hydroxyl, C ₁ -C ₄ alkylthio, amino, methylamino, ethylamino, dimethylamino, di Ethylamino, formyl, acetyl, formylamino, acetylamino, C ₁ -C ₄ alkoxycarbonyl, carboxyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, Compounds with diethylcarbamoyl, nitro or cyano groups. (3) ^R1 is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, hydroxyl, methylthio, ethylthio, amino , methylamino, ethylamino, dimethylamino, formyloxy, acetoxy, methoxycarbonyl, ethoxycarbonyl, carboxyl, carbamoyl, nitro or cyano groups. (4) Compounds in which R ¹ is a hydrogen, fluorine, chlorine, bromine, methyl, methoxy, methylthio, difluoromethoxy, methoxycarbonyl, nitro or cyano group. (5) A compound in which R ² _a is an amino, methylamino, dimethylamino, piperidinyl or morpholinyl group. (6) A compound in which R ² _a is an amino, piperidinyl or morpholinyl group. (7) A compound in which R ² _a is amino. (8) The compound where m is 2. (9) The compound in which m is 1. (10) Compounds in which n is 2-4. (11) Compounds in which n is 2. (12) The ring A is phenyl, naphthyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridyl Compounds with an azinyl, pyrimidinyl or pyridazinyl ring. (13) The compound in which the ring A is a phenyl, naphthyl or pyridyl ring. (14) The compound in which the ring A is a phenyl or pyridyl ring. (15) The compound in which the ring A is a phenyl ring. (16) A compound in which X is oxygen. (17) 3-(2-Aminoethoxy)benzisoxazole,

3-(2-Aminoethylthio)benzisoxazole,

3-(2-Aminoethoxy)-fluorobenzoisoxazole,

3-(2-Aminoethylthio)-fluorobenzisoxazole,

3-(2-Aminoethoxy)-fluoro-methylbenzisoxazole,

3-(2-Aminoethylthio)-fluoro-methylbenzisoxazole,

3-(2-Aminoethoxy)-fluoro-methylthiobenzisoxazole,

3-(2-Aminoethoxy)-fluoro-methoxycarbonylbenzisoxazole,

3-(2-Aminoethoxy)-fluoro-carbamoylbenzisoxazole,

3-(2-Aminoethoxy)-fluoro-cyanobenzisoxazole,

3-(2-Aminoethylthio)-fluoro-cyanobenzisoxazole,

3-(2-Aminoethoxy)-chlorobenzisoxazole,

3-(2-Aminoethylthio)-chlorobenzisoxazole,

3-(2-Aminoethoxy)-dichlorobenzisoxazole,

3-(2-Aminoethylthio)-dichlorobenzisoxazole,

3-(2-Aminoethoxy)-chloro-methylbenzisoxazole,

3-(2-Aminoethylthio)-chloro-methylbenzisoxazole,

3-(2-Aminoethoxy)-chloro-carbamoylbenzisoxazole,

3-(2-Aminoethoxy)-chloro-cyanobenzisoxazole,

3-(2-Aminoethylthio)-chloro-cyanobenzisoxazole,

3-(2-Aminoethoxy)-dichloro-methylbenzisoxazole,

3-(2-Aminoethoxy)-bromobenzisoxazole,

3-(2-Aminoethoxy)-bromo-methylbenzisoxazole,

3-(2-Aminoethoxy)-methylbenzisoxazole,

3-(2-Aminoethylthio)-methylbenzisoxazole,

3-(2-Aminoethoxy)-dimethylbenzisoxazole,

3-(2-Aminoethoxy)-methyl-methoxybenzisoxazole,

3-(2-Aminoethoxy)-methyl-methylthiobenzisoxazole,

3-(2-Aminoethoxy)-methyl-methoxycarbonylbenzisoxazole,

3-(2-Aminoethoxy)-methyl-carbamoylbenzoisoxazole,

3-(2-Aminoethoxy)-methyl-cyanobenzisoxazole,

3-(2-Aminoethoxy)-trifluoromethylbenzisoxazole,

3-(2-Aminoethoxy)-methoxybenzisoxazole,

3-(2-Aminoethylthio)-methoxybenzisoxazole,

3-(2-Aminoethoxy)-difluoromethoxybenzisoxazole,

3-(2-Aminoethoxy)-hydroxybenzoisoxazole,

3-(2-Aminoethoxy)-aminobenzisoxazole,

3-(2-Aminoethylthio)-aminobenzisoxazole,

3-(2-Aminoethoxy)-methylaminobenzisoxazole,

3-(2-Aminoethoxy)-dimethylaminobenzisoxazole,

3-(2-Aminoethoxy)-acetoxybenzisoxazole,

3-(2-Aminoethoxy)-carboxybenzisoxazole,

3-(2-Aminoethoxy)-methoxycarbonylbenzisoxazole,

3-(2-Aminoethoxy)-carbamoylbenzisoxazole,

3-(2-Aminoethoxy)-nitrobenzisoxazole,

3-(2-Aminoethylthio)-nitrobenzisoxazole,

3-(2-Aminoethoxy)-cyanobenzisoxazole,

3-(2-Aminoethoxy)-naphthoisoxazole,

3-(2-Aminoethoxy)-pyridoisoxazole,

3-(2-Aminoethoxy)-chloropyridoisoxazole,

3-(2-Aminoethylthio)-chloropyridisoxazole,

3-(2-Aminoethoxy)-picolineisoxazole, or

3-(2-Aminoethoxy)-trifluoromethylpyridoisoxazole,

1- Compounds in any of the 6 combinations are also preferred, such as the following combinations given below. (17)(1), (5) and (10), (18)(2), (7), (10) and (12), (19)(2), (7), (11) and ( 13), (20)(3), (7), (11) and (13), (21)(3), (7), (8), (11) and (14), (22)(4 ), (7), (11) and (13), (23)(4), (7), (8), (11) and (14), (24)(4), (7), (8 ), (11) and (15).

Typical compounds of the present invention are those shown in the following tables, but are not limited to these compounds.

Abbreviations used in the table are as follows.

Ac: Acetyl

Et: ethyl

Me: methyl

Ph: phenyl

Pip: piperidino

Prj: isopropyl

Mor: Morpholino provided that (R ¹ ) _m represents all 1, 2 or 3 substituents on ring A. 〔Table 1〕 Compound No. (R ¹ ) _m n X

1-1 H 1 O

1-2 H 1 S

1-3 H 2 O

1-4 H 2 S

1-5 H H 3 O

1-6 H 3 S

1-7 H 4 O

1-8 H 4 S

1-9 H H 5 O

1-10 H 5 S

1-11 H H 6 O

1-12 H 6 S

1-13 4-F 2 O

1-14 4-F 2 S

1-15 5-F 2 O

1-16 5-F 4-F 2 O

1-17 5-F 6-F 2 O

1-18 5-F 7-F 2 O

1-19 5-F 4-Cl 2 2 O

1-20 5-F 6-Cl 2 O

1-21 5-F 7-Cl 2 2 O

1-22 5-F 4-Me 2 O

1-23 5-F 6-Me 2 O

1-24 5-F 7-Me 2 O

1-25 5-F 4-OMe 2 O

1-26 5-F 6-OMe 2 O

1-27 5-F 7-OMe 2 O

1-28 5-F 4-CN 2 O

1-29 5-F 6-CN 2 O

1-30 5-F 7-CN 2 O

1-31 5-F 2 S

1-32 5-F 4-F 2 S

1-33 5-F 6-F 2 S

1-34 5-F 7-F 2 S

1-35 5-F 4-Cl 2 S

1-36 5-F 6-Cl 2 S

1-37 5-F 7-C1 2 S

1-38 5-F 4-Me 2 S

1-39 5-F 6-Me 2 S

1-40 5-F 7-Me 2 S

1-41 5-F 4-OMe 2 S

1-42 5-F 6-OMe 2 S

1-43 5-F 7-OMe 2 S

1-44 5-F 4-CN 2 S

1-45 5-F 6-CN 2 S

1-46 5-F 7-CN 2 S

1-47 6-F 2 O

1-48 6-F 2 S

1-49 7-F 2 O

1-50 7-F 2 S

1-51 4-Cl 2 O

1-52 4-Cl 2 S

1-53 5-Cl 2 O

1-54 5-Cl 4-F 2 O

1-55 5-Cl 6-F 2 O

1-56 5-Cl 7-F 2 O

1-57 5-Cl 4-Cl 2 O

1-58 5-Cl 6-Cl 2 O

1-59 5-Cl 7-Cl 2 O

1-60 5-Cl 4-Me 2 O

1-61 5-Cl 6-Me 2 O

1-62 5-Cl 7-Me 2 O

1-63 5-Cl 4-OMe 2 O

1-64 5-Cl 6-OMe 2 O

1-65 5-Cl 7-OMe 2 O

1-66 5-Cl 4-CN 2 O

1-67 5-Cl 6-CN 2 O

1-68 5-Cl 7-CN 2 O

1-69 5-Cl 2 S

1-70 5-Cl 4-F 2 S

1-71 5-Cl 6-F 2 S

1-72 5-Cl 7-F 2 S

1-73 5-Cl 4-Cl 2 S

1-74 5-Cl 6-Cl 2 S

1-75 5-Cl 7-Cl 2 S

1-76 5-Cl 4-Me 2 S

1-77 5-Cl 6-Me 2 S

1-78 5-Cl 7-Me 2 S

1-79 5-Cl 4-OMe 2 S

1-80 5-Cl 6-OMe 2 S

1-81 5-Cl 7-OMe 2 S

1-82 5-Cl 4-CN 2 S

1-83 5-Cl 6-CN 2 S

1-84 5-Cl 7-CN 2 S

1-85 6-Cl 2 O

1-86 6-Cl 7-Cl 2 O

1-87 6-Cl 4-Me 2 O

1-88 6-Cl 5-Me 2 O

1-89 6-Cl 7-Me 2 O

1-90 6-Cl 4-OMe 2 O

1-91 6-Cl 5-OMe 2 O

1-92 6-Cl 7-OMe 2 O

1-93 6-Cl 4-CN 2 O

1-94 6-Cl 5-CN 2 O

1-95 6-Cl 7-CN 2 O

1-96 6-Cl 2 S

1-97 7-Cl 2 O

1-98 7-Cl 4-Me 2 O

1-99 7-Cl 5-Me 2 O

1-100 7-Cl 6-Me 2 O

1-101 7-Cl 4-OMe 2 O

1-102 7-Cl 5-OMe 2 O

1-103 7-Cl 6-OMe 2 O

1-104 7-Cl 4-CN 2 O

1-105 7-Cl 5-CN 2 O

1-106 7-Cl 6-CN 2 O

1-107 7-Cl 2 S

1-108 7-Cl 4-Me 2 S

1-109 7-Cl 5-Me 2 S

1-110 7-Cl 6-Me 2 S

1-111 7-Cl 4-OMe 2 S

1-112 7-Cl 5-OMe 2 S

1-113 7-Cl 6-OMe 2 S

1-114 7-Cl 4-CN 2 S

1-115 7-Cl 5-CN 2 S

1-116 7-Cl 6-CN 2 S

1-117 4-Br 2 O

1-118 4-Br 2 S

1-119 5-Br 2 O

1-120 5-Br 4-F 2 O

1-121 5-Br 6-F 2 O

1-122 5-Br 7-F 2 O

1-123 5-Br 4-Cl 2 O

1-124 5-Br 6-Cl 2 O

1-125 5-Br 7-Cl 2 O

1-126 5-Br 4-Me 2 O

1-127 5-Br 6-Me 2 O

1-128 5-Br 7-Me 2 O

1-129 5-Br 4-OMe 2 O

1-130 5-Br 6-OMe 2 O

1-131 5-Br 7-OMe 2 O

1-132 5-Br 4-CN 2 O

1-133 5-Br 6-CN 2 O

1-134 5-Br 7-CN 2 O

1-135 5-Br 2 S

1-136 6-Br 2 O

1-137 6-Br 2 S

1-138 7-Br 2 O

1-139 7-Br 2 S

1-140 4-Me 2 O

1-141 4-Me 2 S

1-142 5-Me 2 O

1-143 5-Me 6-Me 2 O

1-144 5-Me 7-Me 2 O

1-145 5-Me 4-OMe 2 O

1-146 5-Me 6-OMe 2 O

1-147 5-Me 7-OMe 2 O

1-148 5-Me 4-CN 2 O

1-149 5-Me 6-CN 2 O

1-150 5-Me 7-CN 2 O

1-151 5-Me 2 S

1-152 5-Me 6-Me 2 S

1-153 5-Me 7-Me 2 S

1-154 5-Me 4-OMe 2 S

1-155 5-Me 6-OMe 2 S

1-156 5-Me 7-OMe 2 S

1-157 5-Me 4-CN 2 S

1-158 5-Me 6-CN 2 S

1-159 5-Me 7-CN 2 S

1-160 6-Me 2 O

1-161 6-Me 7-Me 2 O

1-162 6-Me 4-OMe 2 O

1-163 6-Me 5-OMe 2 O

1-164 6-Me 7-OMe 2 O

1-165 6-Me 4-CN 2 O

1-166 6-Me 5-CN 2 O

1-167 6-Me 7-CN 2 O

1-168 6-Me 2 S

1-169 7-Me 2 O

1-170 7-Me 4-OMe 2 O

1-171 7-Me 5-OMe 2 O

1-172 7-Me 6-OMe 2 O

1-173 7-Me 4-CN 2 O

1-174 7-Me 5-CN 2 O

1-175 7-Me 6-CN 2 O

1-176 7-Me 2 S

1-177 7-Me 4-OMe 2 S

1-178 7-Me 5-OMe 2 S

1-179 7-Me 6-OMe 2 S

1-180 7-Me 4-CN 2 S

1-181 7-Me 5-CN 2 S

1-182 7-Me 6-CN 2 S

1-183 4-Et 2 O

1-184 4-Et 2 S

1-185 5-Et 2 O

1-186 5-Et 2 S

1-187 6-Et 2 O

1-188 6-Et 2 S

1-189 7-Et 2 O

1-190 7-Et 2 S

1-191 4-OMe 2 O

1-1 92 4-OMe 2 S

1-193 5-OMe 2 O

1-194 5-OMe 4-CN 2 O

1-195 5-OMe 6-CN 2 O

1-196 5-OMe 7-CN 2 O

1-197 5-OMe 2 S

1-198 6-OMe 2 O

1-199 6-OMe 2 S

1-200 7-OMe 2 O

1-201 7-OMe 4-Me 2 O

1-202 7-OMe 5-OMe 2 O

1-203 7-OMe 6-OMe 2 O

1-204 7-OMe 4-CN 2 O

1-205 7-OMe 5-CN 2 O

1-206 7-OMe 6-CN 2 O

1-207 7-OMe 2 S

1-208 7-OMe 4-Me 2 S

1-209 7-OMe 5-OMe 2 S

1-210 7-OMe 6-Me 2 S

1-211 7-OMe 4-CN 2 S

1-212 7-OMe 5-CN 2 S

1-213 7-OMe 6-CN 2 S

1-214 4-OEt 2 O

1-215 4-OEt 2 S

1-216 5-OEt 2 O

1-217 5-OEt 2 S

1-218 6-OEt 2 O

1-219 6-OEt 2 S

1-220 7-OEt 2 O

1-221 7-OEt 2 S

1-222 4-OCHF ₂ 2 O

1-223 4-OCHF ₂ 2 S

1-224 5-OCHF ₂ 2 O

1-225 5-OCHF ₂ 4-F 2 O

1-226 5-OCHF ₂ 6-F 2 O

1-227 5-OCHF ₂ 7-F 2 O

1-228 5-OCHF ₂ 4-Cl 2 O

1-229 5-OCHF ₂ 6-C1 2 O

1-230 5-OCHF ₂ 7-Cl 2 O

1-231 5-OCHF ₂ 4-Me 2 O

1-232 5-OCHF ₂ 6-Me 2 O

1-233 5-OCHF ₂ 7-Me 2 O

1-234 5-OCHF ₂ 4-OMe 2 O

1-235 5-OCHF ₂ 6-OMe 2 O

1-236 5-OCHF ₂ 7-OMe 2 O

1-237 5-OCHF ₂ 4-CN 2 O

1-238 5-OCHF ₂ 6-CN 2 O

1-239 5-OCHF ₂ 7-CN 2 O

1-240 5-OCHF ₂ 2 S

1-241 6-OCHF ₂ 2 O

1-242 6-OCHF ₂ 2 S

1-243 7-OCHF ₂ 2 O

1-244 7-OCHF ₂ 2 S

1-245 4-OH 2 O

1-246 4-OH 2 S

1-247 5-OH 2 O

1-248 5-OH 4-F 2 O

1-249 5-OH 6-F 2 O

1-250 5-OH 7-F 2 O

1-251 5-OH 4-Cl 2 O

1-252 5-OH 6-C1 2 O

1-253 5-OH 7-C1 2 O

1-254 5-OH 4-Me 2 O

1-255 5-OH 6-Me 2 O

1-256 5-OH 7-Me 2 O

1-257 5-OH 4-OMe 2 O

1-258 5-OH 6-OMe 2 O

1-259 5-OH 7-OMe 2 O

1-260 5-OH 4-CN 2 O

1-261 5-OH 6-CN 2 O

1-262 5-OH 7-CN 2 O

1-263 5-OH 2 S

1-264 6-OH 2 O

1-265 6-OH 2 S

1-266 7-OH 2 O

l-267 7-OH 2 S

1-268 4-SMe 2 O

1-269 4-SMe 5-F 2 O

1-270 4-SMe 6-F 2 O

1-271 4-SMe 7-F 2 O

1-272 4-SMe 5-Cl 2 2 O

1-273 4-SMe 6-Cl 2 2 O

1-274 4-SMe 7-Cl 2 2 O

1-275 4-SMe 5-Me 2 O

1-276 4-SMe 6-Me 2 O

1-277 4-SMe 7-Me 2 O

1-278 4-SMe 5-OMe 2 O

1-279 4-SMe 6-OMe 2 O

1-280 4-SMe 7-OMe 2 O

1-281 4-SMe 5-CN 2 O

1-282 4-SMe 6-CN 2 O

1-283 4-SMe 7-CN 2 O

1-284 4-SMe 2 S

1-285 5-SMe 2 O

1-286 5-SMe 2 S

1-287 6-SMe 2 O

1-288 6-SMe 2 S

1-289 7-SMe 2 O

1-290 7-SMe 2 S

1-291 4-NH ₂ 2 O

1-292 4-NH ₂ 2 S

1-293 5-NH ₂ 2 O

1-294 5-NH ₂ 2 S

1-295 5-NH ₂ 4-F 2 S

1-296 5-NH ₂ 6-F 2 S

1-297 5-NH ₂ 7-F 2 S

1-298 5-NH ₂ 4-Cl 2 S

1-299 5-NH ₂ 6-Cl 2 S

1-300 5-NH ₂ 7-Cl 2 S

1-301 5-NH ₂ 4-Me 2 S

1-302 5-NH ₂ 6-Me 2 S

1-303 5-NH ₂ 7-Me 2 S

1-304 5-NH ₂ 4-OMe 2 S

1-305 5-NH ₂ 6-OMe 2 S

1-306 5-NH ₂ 7-OMe 2 S

1-307 5-NH ₂ 4-CN 2 S

1-308 5-NH ₂ 6-CN 2 S

1-309 5-NH ₂ 7-CN 2 S

1-310 6-NH ₂ 2 O

1-311 6-NH ₂ 2 S

1-312 7-NH ₂ 2 O

1-313 7-NH ₂ 4-F 2 O

1-314 7-NH ₂ 5-F 2 O

1-315 7-NH ₂ 6-F 2 O

1-316 7-NH ₂ 4-Cl 2 O

1-317 7-NH ₂ 5-Cl 2 O

1-318 7-NH ₂ 6-Cl 2 O

1-319 7-NH ₂ 4-Me 2 O

1-320 7-NH ₂ 5-Me 2 O

1-321 7-NH ₂ 6-Me 2 O

1-322 7-NH ₂ 4-OMe 2 O

1-323 7-NH ₂ 5-OMe 2 O

1-324 7-NH ₂ 6-OMe 2 O

1-325 7-NH ₂ 4-CN 2 O

1-326 7-NH ₂ 5-CN 2 O

1-327 7-NH ₂ 6-CN 2 O

1-328 7-NH ₂ 2 S

1-329 7-NH ₂ 4-F 2 S

1-330 7-NH ₂ 5-F 2 S

1-331 7-NH ₂ 6-F 2 S

1-332 7-NH ₂ 4-Cl 2 S

1-333 7-NH ₂ 5-Cl 2 S

1-334 7-NH ₂ 6-C1 2 S

1-335 7-NH ₂ 4-Me 2 S

1-336 7-NH ₂ 5-Me 2 S

1-337 7-NH ₂ 6-Me 2 S

1-338 7-NH ₂ 4-OMe 2 S

1-339 7-NH ₂ 5-OMe 2 S

1-340 7-NH ₂ 6-OMe 2 S

1-341 7-NH ₂ 4-CN 2 S

1-342 7-NH ₂ 5-CN 2 S

1-343 7-NH ₂ 6-CN 2 S

1-344 4-NHMe 2 O

1-345 4-NHMe 2 S

1-346 5-NHMe 2 O

1-347 5-NHMe 4-F 2 O

1-348 5-NHMe 6-F 2 O

1-349 5-NHMe 7-F 2 O

1-350 5-NHMe 4-Cl 2 O

1-351 5-NHMe 6-Cl 2 O

1-352 5-NHMe 7-Cl 2 O

1-353 5-NHMe 4-Me 2 O

1-354 5-NHMe 6-Me 2 O

1-355 5-NHMe 7-Me 2 O

1-356 5-NHMe 4-OMe 2 O

1-357 5-NHMe 6-OMe 2 O

1-358 5-NHMe 7-OMe 2 O

1-359 5-NHMe 4-CN 2 O

1-360 5-NHMe 6-CN 2 O

1-361 5-NHMe 7-CN 2 O

1-362 5-NHMe 2 S

1-363 6-NHMe 2 O

1-364 6-NHMe 2 S

1-365 7-NHMe 2 O

1-366 7-NHMe 4-F 2 O

1-367 7-NHMe 5-F 2 O

1-368 7-NHMe 6-F 2 O

1-369 7-NHMe 4-Cl 2 O

1-370 7-NHMe 5-Cl 2 O

1-371 7-NHMe 6-Cl 2 O

1-372 7-NHMe 4-Me 2 O

1-373 7-NHMe 5-Me 2 O

1-374 7-NHMe 6-Me 2 O

1-375 7-NHMe 4-OMe 2 O

1-376 7-NHMe 5-OMe 2 O

1-377 7-NHMe 6-OMe 2 O

1-378 7-NHMe 4-CN 2 O

1-379 7-NHMe 5-CN 2 O

1-380 7-NHMe 6-CN 2 O

1-381 7-NHMe 2 S

1-382 4-OAc 2 O

1-383 4-OAc 2 S

1-384 5-OAc 2 O

1-385 5-OAc 4-F 2 O

1-386 5-OAc 6-F 2 O

1-387 5-OAc 7-F 2 O

1-388 5-OAc 4-Cl 2 O

1-389 5-OAc 6-Cl 2 O

1-390 5-OAc 7-Cl 2 O

1-391 5-OAc 4-Me 2 O

1-392 5-OAc 6-Me 2 O

1-393 5-OAc 7-Me 2 O

1-394 5-OAc 4-OMe 2 O

1-395 5-OAc 6-OMe 2 O

1-396 5-OAc 7-OMe 2 O

1-397 5-OAc 4-CN 2 O

1-398 5-OAc 6-CN 2 O

1-399 5-OAc 7-CN 2 O

1-400 5-OAc 2 S

1-401 6-OAc 2 O

1-402 6-OAc 2 S

1-403 7-OAc 2 O

1-404 7-OAc 2 S

1-405 4-COOMe 2 O

1-406 4-COOMe 5-F 2 O

1-407 4-COOMe 6-F 2 O

1-408 4-COOMe 7-F 2 O

1-409 4-COOMe 5-Cl 2 O

1-41O 4-COOMe 6-Cl 2 O

1-411 4-COOMe 7-Cl 2 O

1-412 4-COOMe 5-Me 2 O

1-413 4-COOMe 6-Me 2 O

1-414 4-COOMe 7-Me 2 O

1-415 4-COOMe 5-OMe 2 O

1-416 4-COOMe 6-OMe 2 O

1-417 4-COOMe 7-OMe 2 O

1-418 4-COOMe 5-CN 2 O

1-419 4-COOMe 6-CN 2 O

1-420 4-COOMe 7-CN 2 O

1-421 4-COOMe 2 S

1-422 5-COOMe 2 O

1-423 5-COOMe 4-F 2 O

1-424 5-COOMe 6-F 2 O

1-425 5-COOMe 7-F 2 O

1-426 5-COOMe 4-Cl 2 O

1-427 5-COOMe 6-Cl 2 O

1-428 5-COOMe 7-Cl 2 O

1-429 5-COOMe 4-Me 2 O

1-430 5-COOMe 6-Me 2 O

1-431 5-COOMe 7-Me 2 O

1-432 5-CCOMe 4-OMe 2 O

1-433 5-COOMe 6-OMe 2 O

1-434 5-COOMe 7-OMe 2 O

1-435 5-COOMe 4-CN 2 O

1-436 5-COOMe 6-CN 2 O

1-437 5-COOMe 7-CN 2 O

1-438 5-COOMe 2 S

1-439 6-COOMe 2 O

1-440 6-COOMe 2 S

1-441 7-COOMe 2 O

1-442 7-COOMe 4-F 2 O

1-443 7-COOMe 5-F 2 O

1-444 7-COOMe 6-F 2 O

1-445 7-COOMe 4-Cl 2 O

1-446 7-COOMe 5-Cl 2 O

1-447 7-COOMe 5-Br 2 O

1-448 7-COOMe 4-Me 2 O

1-449 7-COOMe 5-Me 2 O

1-450 7-COOMe 6-Me 2 O

1-451 7-COOMe 4-OMe 2 O

1-452 7-COOMe 5-OMe 2 O

1-453 7-COOMe 6-OMe 2 O

1-454 7-COOMe 4-CN 2 O

1-455 7-COOMe 5-CN 2 O

1-456 7-COOMe 6-CN 2 O

1-457 7-COOMe 2 S

1-458 4-COOH 2 O

1-459 4-COOH 2 S

1-460 5-COOH 2 O

1-461 5-COOH 2 S

1-462 6-COOH 2 O

1-463 6-COOH 2 S

1-464 7-COOH 2 O

1-465 5-CF ₃ 4-Me 2 O

1-466 5-CF ₃ 7-Me 2 O

1-467 5-CF ₃ 4-CN 2 O

1-468 5-CF ₃ 7-CN 2 O

1-469 5-CF ₃ 4-CF ₃ 2 O

1-470 5-CF ₃ 7-CF ₃ 2 O

1-471 4-CF ₃ 2 O

1-472 4-CF ₃ 5-Me 2 O

1-473 4-CF ₃ 5-F 2 O

1-474 4-CF ₃ 5-OMe 2 O

1-475 4-CF ₃ 5-SMe 2 O

1-476 4-CF ₃ 5-CN 2 O

1-477 4-CF ₃ 5-N(Me) ₂ 2 O

1-478 4-CF ₃ 5-NO ₂ 2 O

1-479 4-CF ₃ 5-Cl 2 O

1-480 7-CF ₃ 2 O

1-481 4-CONH ₂ 2 O

1-482 4-CONH ₂ 5-F 2 O

1-483 4-CONH ₂ 6-F 2 O

1-484 4-CONH ₂ 7-F 2 O

1-485 4-CONH ₂ 5-Cl 2 O

1-486 4-CONH ₂ 6-Cl 2 O

1-487 4-CONH ₂ 7-Cl 2 O

1-488 4-CONH ₂ 5-Me 2 O

1-489 4-CONH ₂ 6-Me 2 O

1-490 4-CONH ₂ 7-Me 2 O

1-491 4-CONH ₂ 5-OMe 2 O

1-492 4-CONH ₂ 6-OMe 2 O

1-493 4-CONH ₂ 7-OMe 2 O

1-494 4-CONH ₂ 5-CN 2 O

1-495 4-CONH ₂ 6-CN 2 O

1-496 4-CONH ₂ 7-CN 2 O

1-497 4-CONH ₂ 2 S

1-498 5-CONH ₂ 2 O

1-499 5-CONH ₂ 2 S

1-500 6-CONH ₂ 2 O

1-501 6-CONH ₂ 2 S

1-502 7-CONH ₂ 2 O

1-503 5-SMe 4-Me 2 O

1-504 5-SMe 5-CN 2 O

1-505 5-SMe 7-Me 2 O

1-506 5-SMe 7-CN 2 O

1-507 5-CN 4-Me 2 O

1-508 5-CN 4-CN 2 O

1-509 7-CONH ₂ 4-Me 2 O

1-510 5-CN 7-CN 2 O

1-511 7-CONH ₂ 6-Me 2 O

1-512 7-SMe 5-Cl 2 O

1-513 7-SMe 5-Br 2 O

1-514 7-SMe 5-NO ₂ 2 O

1-515 7-SMe 5-OMe 2 O

1-516 7-SMe 5-CN 2 O

1-517 7-SMe 4-CN 2 O

1-518 7-CONH ₂ 2 S

1-519 4-NO ₂ 2 O

1-520 4-NO ₂ 2 S

1-521 5-NO ₂ 2 O

1-522 5-NO ₂ 4-F 2 O

1-523 5-NO ₂ 6-F 2 O

1-524 5-NO ₂ 7-F 2 O

1-525 5-NO ₂ 4-Cl 2 O

1-526 5-NO ₂ 6-Cl 2 O

1-527 5-NO ₂ 7-Cl 2 O

1-528 5-NO ₂ 4-Me 2 O

1-529 5-NO ₂ 6-Me 2 O

1-530 5-NO ₂ 7-Me 2 O

1-531 5-NO ₂ 4-OMe 2 O

1-532 5-NO ₂ 6-OMe 2 O

1-533 5-NO ₂ 7-OMe 2 O

1-534 5-NO ₂ 4-CN 2 O

1-535 5-NO ₂ 6-CN 2 O

1-536 5-NO ₂ 7-CN 2 O

1-537 5-NO ₂ 2 S

1-538 5-NO ₂ 4-F 2 S

1-539 5-NO ₂ 6-F 2 S

1-540 5-NO ₂ 7-F 2 S

1-541 5-NO ₂ 4-Cl 2 S

1-542 5-NO ₂ 6-Cl 2 S

1-543 5-NO ₂ 7-Cl 2 S

1-544 5-NO ₂ 4-Me 2 S

1-545 5-NO ₂ 6-Me 2 S

1-546 5-NO ₂ 7-Me 2 S

1-547 5-NO ₂ 4-OMe 2 S

1-548 5-NO ₂ 6-OMe 2 S

1-549 5-NO ₂ 7-OMe 2 S

1-550 5-NO ₂ 4-CN 2 S

1-551 5-NO ₂ 6-CN 2 S

1-552 5-NO ₂ 7-CN 2 S

1-553 6-NO ₂ 2 O

1-554 6-NO ₂ 2 S

1-555 7-NO ₂ 2 O

1-556 7-NO ₂ 2 S

1-557 7-NO ₂ 4-F 2 S

1-558 7-NO ₂ 5-F 2 S

1-559 7-NO ₂ 6-F 2 S

1-560 7-NO ₂ 4-Cl 2 S

1-561 7-NO ₂ 5-Cl 2 S

1-562 7-NO ₂ 6-Cl 2 S

1-563 7-NO ₂ 4-Me 2 S

1-564 7-NO ₂ 5-Me 2 S

1-565 7-NO ₂ 6-Me 2 S

1-566 7-NO ₂ 4-OMe 2 S

1-567 7-NO ₂ 5-OMe 2 S

1-568 7-NO ₂ 6-OMe 2 S

1-569 7-NO ₂ 4-CN 2 S

1-570 7-NO ₂ 5-CN 2 S

1-571 7-NO ₂ 6-CN 2 S

1-572 4-CN 2 O

1-573 4-CN 2 S

1-574 5-CN 2 O

1-575 5-CN 2 S

1-576 6-CN 2 O

1-577 6-CN 2 S

1-578 7-CN 2 O

1-579 7-CN 2 S

1-580 5-OMe 4-Me 2 O

1-581 7-Me 4-Me 2 O

1-582 6-Me 4-Me 2 O

1-583 5-Me 4-Me 2 O

1-584 4-N(Me) ₂ 2 O

1-585 4-N(Me) ₂ 2 S

1-586 5-N(Me) ₂ 2 O

1-587 5-N(Me) ₂ 2 S

1-588 6-N(Me) ₂ 2 O

1-589 6-N(Me) ₂ 2 S

1-590 7-N(Me) ₂ 2 O

1-591 7-N(Me) ₂ 2 S

1-592 4-Cl 6-Me 2 O

1-593 4-Cl 6-Me 2 S

1-594 4-F 5-Me 2 O

1-595 4-F 5-Me 2 S

1-596 4-F 7-Me 2 O

1-597 4-F 7-Me 2 S

1-598 5-Cl 7-CONH ₂ 2 O

1-599 5-Cl 7-CONH ₂ 2 S

1-600 5-F 4-CS ₂ Me 2 O

1-601 5-F 4-CS ₂ Me 2 S

1-602 5-F 4-CF ₂ 2 S

1-603 7-CF ₃ 2 S

1-604 4-F 7-Cl 2 O

1-605 4-F 7-Cl 2 S

1-606 4-F 7-CN 2 O

1-607 4-F 7-CN 2 S

1-608 7-F 4-Cl 2 O

1-609 7-F 4-Cl 2 S

1-61O 7-F 4-Me 2 O

1-611 7-F 4-Me 2 S

1-612 7-F 4-CN 2 O

1-613 7-F 4-CN 2 S

1-614 4-Me 7-CN 2 O

1-615 4-Me 7-CN 2 S

1-616 5-F 7-F 4-Me 2 O

1-617 5-F 7-F 4-Me 2 S

1-618 5-Cl 7-Cl 4-Me 2 O

1-619 5-Cl 7-Cl 4-Me 2 S

1-620 5-Cl 7-Cl 4-COOH 2 O

1-621 5-Cl 7-Cl 4-COOH 2 S

1-622 5-Cl 7-Cl 4-COOMe 2 O

1-623 5-Cl 7-Cl 4-COOMe 2 S

1-624 5-Cl 7-Cl 4-CONH ₂ 2 O

1-625 5-Cl 7-Cl 4-CONH ₂ 2 S

1-626 5-Cl 7-Cl 4-CN 2 O

1-627 5-Cl 7-Cl 4-CN 2 S [Table 2] Compound No. (R ¹ ) _m n X

2-1 H H 1 O

2-2 H 1 S

2-3 H 2 O

2-4 4-F 2 O

2-5 5-F 2 O

2-6 6-F 2 O

2-7 7-F 2 O

2-8 8-F 2 O

2-9 9-F 2 O

2-10 4-Cl 2 O

2-11 5-Cl 2 O

2-12 6-Cl 2 O

2-13 7-Cl 2 O

2-14 8-Cl 2 O

2-15 9-Cl 2 O

2-16 5-NHMe 2 O

2-17 6-NHMe 2 O

2-18 7-NHMe 2 O

2-19 4-Me 2 O

2-20 5-Me 2 O

2-21 6-Me 2 O

2-22 7-Me 2 O

2-23 8-Me 2 O

2-24 9-Me 2 O

2-25 5-N(Me) ₂ 2 O

2-26 6-N(Me) ₂ 2 O

2-27 7-N(Me) ₂ 2 O

2-28 8-N(Me) ₂ 2 O

2-29 4-OMe 2 O

2-30 5-OMe 2 O

2-31 6-OMe 2 O

2-32 7-OMe 2 O

2-33 8-OMe 2 O

2-34 9-OMe 2 O

2-35 5-OEt 2 O

2-36 6-OEt 2 O

2-37 7-OEt 2 O

2-38 8-OEt 2 O

2-39 5-OCHF ₂ 2 O

2-40 6-OCHF ₂ 2 O

2-41 7-OCHF ₂ 2 O

2-42 8-OCHF ₂ 2 O

2-43 5-NO ₂ 2 O

2-44 6-NO ₂ 2 O

2-45 7-NO ₂ 2 O

2-46 8-NO ₂ 2 O

2-47 4-CN 2 O

2-48 5-CN 2 O

2-49 6-CN 2 O

2-50 7-CN 2 O

2-51 8-CN 2 O

2-52 9-CN 2 O

2-53 H 2 S

2-54 4-F 2 S

2-55 5-F 2 S

2-56 6-F 2 S

2-57 7-F 2 S

2-58 8-F 2 S

2-59 9-F 2 S

2-60 4-Cl 2 S

2-61 5-Cl 2 S

2-62 6-Cl 2 S

2-63 7-Cl 2 S

2-64 8-Cl 2 S

2-65 9-Cl 2 S

2-66 5-NHMe 2 S

2-67 6-NHMe 2 S

2-68 7-NHMe 2 S

2-69 4-Me 2 S

2-70 5-Me 2 S

2-71 6-Me 2 S

2-72 7-Me 2 S

2-73 8-Me 2 S

2-74 9-Me 2 S

2-75 5-N(Me) ₂ 2 S

2-76 6-N(Me) ₂ 2 S

2-77 7-N(Me) ₂ 2 S

2-78 8-N(Me) ₂ 2 S

2-79 4-OMe 2 S

2-80 5-OMe 2 S

2-81 6-OMe 2 S

2-82 7-OMe 2 S

2-83 8-OMe 2 S

2-84 9-OMe 2 S

2-85 5-OEt 2 S

2-86 6-OEt 2 S

2-87 7-OEt 2 S

2-88 8-OEt 2 S

2-89 5-OCHF ₂ 2 S

2-90 6-OCHF ₂ 2 S

2-91 7-OCHF ₂ 2 S

2-92 8-OCHF ₂ 2 S

2-93 5-NO ₂ 2 S

2-94 6-NO ₂ 2 S

2-95 7-NO ₂ 2 S

2-96 8-NO ₂ 2 S

2-97 4-CN 2 S

2-98 5-CN 2 S

2-99 6-CN 2 S

2-100 7-CN 2 S

2-101 8-CN 2 S

2-102 9-CN 2 S

2-103 H 3 O

2-104 H 3 S

2-105 H 4 O

2-106 H 4 S

2-107 H 5 O

2-108 H 5 S

2-109 H 6 O

2-110 H 6 S [Table 3] Compound No. (R ¹ ) _m n X

3-1 H 1 O

3-2 H 2 O

3-3 H 2 S

3-4 H H 3 O

3-5 4-F 2 O

3-6 4-F 2 S

3-7 4-F 3 O

3-8 4-F 4 O

3-9 5-F 2 O

3-10 5-F 2 S

3-11 5-F 3 O

3-12 6-F 2 O

3-13 6-F 2 S

3-14 6-F 3 O

3-15 4-Cl 2 O

3-16 4-Cl 2 S

3-17 4-Cl 3 O

3-18 5-Cl 2 O

3-19 5-Cl 2 S

3-20 5-Cl 3 O

3-21 6-Cl 2 O

3-22 6-Cl 2 S

3-23 6-Cl 3 O

3-24 4-Cl 6-Cl 2 O

3-25 4-Cl 6-Cl 2 S

3-26 4-Br 2 O

3-27 4-Br 2 S

3-28 5-Br 2 O

3-29 5-Br 2 S

3-30 5-Br 3 O

3-31 6-Br 2 O

3-32 6-Br 2 S

3-33 6-Br 3 O

3-34 4-Br 6-Cl 2 O

3-35 4-Br 6-Cl 2 S

3-36 4-Me 2 O

3-37 4-Me 2 S

3-38 5-Me 2 O

3-39 5-Me 2 S

3-40 5-Me 3 O

3-41 6-Me 2 O

3-42 6-Me 2 S

3-43 6-Me 3 O

3-44 6-Me 4-Cl 2 O

3-45 6-Me 4-Cl 2 S

3-46 4-CN 2 O

3-47 4-CN 2 S

3-48 5-CN 2 O

3-49 5-CN 2 S

3-50 5-CN 3 O

3-51 6-CN 2 O

3-52 6-CN 2 S

3-53 6-CN 3 O

3-54 6-CN 4-Cl 2 O

3-55 6-Et 4-Cl 2 S

3-56 4-OMe 2 O

3-57 4-OMe 2 S

3-58 5-OMe 2 O

3-59 5-OMe 2 S

3-60 5-OMe 3 O

3-61 6-OMe 2 O

3-62 6-OMe 2 S

3-63 6-OMe 3 O

3-64 4-OEt 2 O

3-65 4-OEt 2 S

3-66 5-OEt 2 O

3-67 5-OEt 2 S

3-68 5-OEt 3 O

3-69 6-OEt 2 O

3-70 6-OEt 2 S

3-71 6-OEt 3 O

3-72 4-NO ₂ 2 O

3-73 4-NO ₂ 2 S

3-74 4-NO ₂ 3 O

3-75 5-NO ₂ 2 O

3-76 5-NO ₂ 2 S

3-77 5-NO ₂ 3 O

3-78 6-NO ₂ 2 O

3-79 6-NO ₂ 2 S

3-80 6-NO ₂ 3 O

3-81 4-NO ₂ 6-Cl 2 O

3-82 4-NO ₂ 6-Cl 2 S

3-83 4-CF ₃ 2 O

3-84 4-CF ₃ 2 S

3-85 5-CF ₃ 2 O

3-86 5-CF ₃ 2 S

3-87 5-CF ₃ 3 O

3-88 6-CF ₃ 2 O

3-89 6-CF ₃ 2 S

化合物号    (R¹)_m              n    X3-90 6-CF ₃ 3 O [Table 4]

Compound No. (R ¹ ) _m n X

4-1 H 1 O

4-2 H 2 O

4-3 H 2 S

4-4 H H 3 O

4-5 5-F 2 O

4-6 5-F 2 S

4-7 5-F 3 O

4-8 6-F 2 O

4-9 6-F 2 S

4-1O 6-F 3 O

4-11 7-Cl 2 O

4-12 7-Cl 2 S

4-13 7-Cl 3 O

4-14 5-Cl 2 O

4-15 5-Cl 2 S

4-16 5-Cl 3 O

4-17 6-Cl 2 O

4-18 6-Cl 2 S

4-19 6-Cl 3 O

4-20 7-Br 2 O

4-21 7-Br 2 S

4-22 5-Br 2 O

4-23 5-Br 2 S

4-24 5-Br 3 O

4-25 6-Br 2 O

4-26 6-Br 2 S

4-27 6-Br 3 O

4-28 7-Br 6-Cl 2 O

4-29 7-Br 6-Cl 2 S

4-30 7-Me 2 O

4-31 7-Me 2 S

4-32 5-Me 2 O

4-33 5-Me 2 S

4-34 5-Me 3 O

4-35 6-Me 2 O

4-36 6-Me 2 S

4-37 6-Me 3 O

4-38 6-Me 7-Cl 2 O

4-39 6-Me 7-Cl 2 S

4-40 7-CN 2 O

4-41 7-CN 2 S

4-42 5-CN 2 O

4-43 5-CN 2 S

4-44 5-CN 3 O

4-45 6-CN 2 O

4-46 6-CN 2 S

4-47 6-CN 3 O

4-48 6-CN 7-Cl 2 O

4-49 6-Et 7-Cl 2 S

4-50 7-OMe 2 O

4-51 7-OMe 2 S

4-52 5-OMe 2 O

4-53 5-OMe 2 S

4-54 5-OMe 3 O

4-55 6-OMe 2 O

4-56 6-OMe 2 S

4-57 6-OMe 3 O

4-58 7-OEt 2 O

4-59 7-OEt 2 S

4-60 5-OEt 2 O

4-61 5-OEt 2 S

4-62 5-OEt 3 O

4-63 6-OEt 2 O

4-64 6-OEt 2 S

4-65 6-OEt 3 O

4-66 7-NO ₂ 2 O

4-67 7-NO ₂ 2 S

4-68 7-NO ₂ 3 O

4-69 5-NO ₂ 2 O

4-70 5-NO ₂ 2 S

4-71 5-NO ₂ 3 O

4-72 6-NO ₂ 2 O

4-73 6-NO ₂ 2 S

4-74 6-NO ₂ 3 O

4-75 7-NO ₂ 6-Cl 2 O

化合物号    (R¹)_m              n     X4-76 7-NO ₂ 6-Cl 2 S [Table 5]

Compound No. (R ¹ ) _m n X

5-1 H 1 O

5-2 H 2 O

5-3 H 2 S

5-4 H H 3 O

5-5 4-F 2 O

5-6 4-F 2 S

5-7 4-F 3 O

5-8 6-F 2 O

5-9 6-F 2 S

5-10 6-F 3 O

5-11 7-Cl 2 O

5-12 7-Cl 2 S

5-13 7-Cl 3 O

5-14 4-Cl 2 O

5-15 4-Cl 2 S

5-16 4-Cl 3 O

5-17 6-Cl 2 O

5-18 6-Cl 2 S

5-19 6-Cl 3 O

5-20 7-Br 2 O

5-21 7-Br 2 S

5-22 4-Br 2 O

5-23 4-Br 2 S

5-24 4-Br 3 O

5-25 6-Br 2 O

5-26 6-Br 2 S

5-27 6-Br 3 O

5-28 7-Br 6-Cl 2 O

5-29 7-Br 6-Cl 2 S

5-30 7-Me 2 O

5-31 7-Me 2 S

5-32 4-Me 2 O

5-33 4-Me 2 S

5-34 4-Me 3 O

5-35 6-Me 2 O

5-36 6-Me 2 S

5-37 6-Me 3 O

5-38 6-Me 7-Cl 2 O

5-39 6-Me 7-Cl 2 S

5-40 7-CN 2 O

5-41 7-CN 2 S

5-42 4-CN 2 O

5-43 4-CN 2 S

5-44 4-CN 3 O

5-45 6-CN 2 O

5-46 6-CN 2 S

5-47 6-CN 3 O

5-48 6-CN 7-Cl 2 O

5-49 6-Et 7-Cl 2 S

5-50 7-OMe 2 O

5-51 7-OMe 2 S

5-52 4-OMe 2 O

5-53 4-OMe 2 S

5-54 4-OMe 3 O

5-55 6-OMe 2 O

5-56 6-OMe 2 S

5-57 6-OMe 3 O

5-58 7-OEt 2 O

5-59 7-OEt 2 S

5-60 4-OEt 2 O

5-61 4-OEt 2 S

5-62 4-OEt 3 O

5-63 6-OEt 2 O

5-64 6-OEt 2 S

5-65 6-OEt 3 O

5-66 7-NO ₂ 2 O

5-67 7-NO ₂ 2 S

5-68 7-NO ₂ 3 O

5-69 4-NO ₂ 2 O

5-70 4-NO ₂ 2 S

5-71 4-NO ₂ 3 O

5-72 6-NO ₂ 2 O

5-73 6-NO ₂ 2 S

5-74 6-NO ₂ 3 O

5-75 7-NO ₂ 6-Cl 2 O

5-76 7-NO ₂ 6-Cl 2 S [Table 6] Compound No. (R ¹ ) _m n X

6-1 H H 1 O

6-2 H 2 O

6-3 H H 2 S

6-4 H H 3 O

6-5 4-F 2 O

6-6 4-F 2 S

6-7 4-F 3 O

6-8 5-F 2 O

6-9 5-F 2 S

6-10 5-F 3 O

6-11 7-Cl 2 O

6-12 7-Cl 2 S

6-13 7-Cl 3 O

6-14 4-Cl 2 O

6-15 4-Cl 2 S

6-16 4-Cl 3 O

6-17 5-Cl 2 O

6-18 5-Cl 2 S

6-19 5-Cl 3 O

6-20 7-Br 2 O

6-21 7-Br 2 S

6-22 4-Br 2 O

6-23 4-Br 2 S

6-24 4-Br 3 O

6-25 5-Br 2 O

6-26 5-Br 2 S

6-27 5-Br 3 O

6-28 7-Br 5-Cl 2 O

6-29 7-Br 5-Cl 2 S

6-30 7-Me 2 O

6-31 7-Me 2 S

6-32 4-Me 2 O

6-33 4-Me 2 S

6-34 4-Me 3 O

6-35 5-Me 2 O

6-36 5-Me 2 S

6-37 5-Me 3 O

6-38 5-Me 7-Cl 2 O

6-39 5-Me 7-Cl 2 S

6-40 7-CN 2 O

6-41 7-CN 2 S

6-42 4-CN 2 O

6-43 4-CN 2 S

6-44 4-CN 3 O

6-45 5-CN 2 O

6-46 5-CN 2 S

6-47 5-CN 3 O

6-48 5-CN 7-Cl 2 O

6-49 5-Et 7-Cl 2 S

6-50 7-OMe 2 O

6-51 7-OMe 2 S

6-52 4-OMe 2 O

6-53 4-OMe 2 S

6-54 4-OMe 3 O

6-55 5-OMe 2 O

6-56 5-OMe 2 S

6-57 5-OMe 3 O

6-58 7-OEt 2 O

6-59 7-OEt 2 S

6-60 4-OEt 2 O

6-61 4-OEt 2 S

6-62 4-OEt 3 O

6-63 5-OEt 2 O

6-64 5-OEt 2 S

6-65 5-OEt 3 O

6-66 7-NO ₂ 2 O

6-67 7-NO ₂ 2 S

6-68 7-NO ₂ 3 O

6-69 4-NO ₂ 2 O

6-70 4-NO ₂ 2 S

6-71 4-NO ₂ 3 O

6-72 5-NO ₂ 2 O

6-73 5-NO ₂ 2 S

6-74 5-NO ₂ 3 O

6-75 7-NO ₂ 5-Cl 2 O

化合物号    (R¹)_m         n    X6-76 7-NO ₂ 5-Cl 2 S [Table 7]

Compound No. (R ¹ ) _m n X

7-1 H 2 O

7-2 H 2 S

7-3 5-F 2 O

7-4 5-F 2 S

7-5 6-F 2 O

7-6 6-F 2 S

7-7 5-Cl 2 O

7-8 5-Cl 2 S

7-9 6-Cl 2 O

7-10 6-Cl 2 S

7-11 6-Cl 3 O

7-12 5-Br 2 O

7-13 5-Br 2 S

7-14 6-Br 2 O

7-15 6-Br 2 S

7-16 5-Me 2 O

7-17 5-Me 2 S

7-18 6-Me 2 O

7-19 6-Me 2 S

7-20 5-Et 2 O

7-21 5-Et 2 S

7-22 6-Et 2 O

7-23 6-Et 2 S

7-24 5-OMe 2 O

7-25 5-OMe 2 S

7-26 6-OMe 2 O

7-27 6-OMe 2 S

7-28 5-OEt 2 O

7-29 5-OEt 2 S

7-30 6-OEt 2 O

7-31 6-OEt 2 S

7-32 5-NO ₂ 2 O

7-33 5-NO ₂ 2 S

7-34 6-NO ₂ 2 O

7-35 6-NO ₂ 2 S [Table 8] Compound No. (R ¹ ) _m n X

8-1 H 2 O

8-2 H 2 S

8-3 4-F 2 O

8-4 4-F 2 O

8-5 5-F 2 O

8-6 5-F 2 S

8-7 4-Cl 2 O

8-8 5-Cl 2 O

8-9 4-Br 2 O

8-10 4-Br 2 S

8-11 5-Br 2 O

8-12 5-Br 2 S

8-13 4-Me 2 O

8-14 4-Me 2 S

8-15 5-Me 2 O

8-16 5-Me 2 S

8-17 4-Et 2 O

8-18 4-Et 2 S

8-19 5-Et 2 O

8-20 5-Et 2 S

8-21 4-OMe 2 O

8-22 4-OMe 2 S

8-23 5-OMe 2 O

8-24 5-OMe 2 S

8-25 4-OEt 2 O

8-26 4-OEt 2 S

8-27 5-OEt 2 O

8-28 5-OEt 2 S

8-29 4-NO ₂ 2 O

8-30 4-NO ₂ 2 S

8-31 5-NO ₂ 2 O

化合物号    (R¹)_m            n     R² _bX8-32 5-NO ₂ 2 S [Table 9]

Compound No. (R ¹ ) _m n R ² _b X

9-1 H H 2 2 NHMe O

_9-2H2NMe2O

9-3 H H 2 2 Pip O

9-4 H H 2 2 Mor O

9-5 H H 2 2 NHMe S

_9-6H2NMe2S

9-7 H H 2 2 Pip S

9-8 H H 2 2 Mor S

9-9 4-F 2 Pip O

9-10 4-F 2 2 Mor O

9-11 4-F 2 Pip S

9-12 4-F 2 2 Mor S

9-13 5-F 2 2 NHMe O

9-14 5-F 2 NMe ₂ O

9-15 5-F 2 Pip O

9-16 5-F 2 2 Mor O

9-17 5-F 2 2 NHMe S

9-18 5-F 2 NMe ₂ S

9-19 6-F 2 2 NHMe O

9-20 6-F 2 NMe ₂ O

9-22 6-F 2 2 Mor O

9-23 6-F 2 NHMe S

9-24 6-F 2 NMe ₂ S

9-25 7-F 2 NHMe O

9-26 7-F 2 NMe ₂ O

9-27 7-F 2 Pip O

9-28 7-F 2 Mor O

9-29 5-F 7-Cl 2 NHMe O

9-30 5-F 7-Cl 2 NMe ₂ O

9-31 5-F 7-Cl 2 Pip O

9-32 5-F 7-Cl 2 Mor O

9-33 5-F 7-Cl 2 NHMe S

9-34 5-F 7-Cl 2 NMe ₂ S

9-35 7-F 5-Cl 2 Pip O

9-36 7-F 5-Cl 2 Mor O

9-37 4-Cl 2 2 NHMe O

9-38 4-Cl 2 NMe ₂ O

9-39 4-Cl 2 Pip O

9-40 4-Cl 2 Mor O

9-41 4-Cl 2 2 NHMe S

9-42 4-Cl 2 NMe ₂ S

9-43 5-Cl 2 2 NHMe O

9-44 5-Cl 2 NMe ₂ O

9-45 5-Cl 2 Pip O

9-46 5-Cl 2 2 Mor O

9-47 5-Cl 2 2 NHMe S

9-48 5-Cl 2 NMe ₂ S

9-49 6-Cl 2 2 NHMe O

9-50 6-Cl 2 NMe ₂ O

9-51 6-Cl 2 Pip O

9-52 6-Cl 2 2 Mor O

9-53 7-Cl 2 2 NHMe O

9-54 7-Cl 2 NMe ₂ O

9-55 7-Cl 2 2 Pip O

9-56 7-Cl 2 2 Mor O

9-57 4-Cl 6-Cl 2 NHMe O

9-58 4-Cl 6-Cl 2 NMe ₂ O

9-59 4-Cl 6-Cl 2 Pip O

9-60 4-Cl 6-Cl 2 Mor O

9-61 5-Cl 7-Cl 2 NHMe O

9-62 5-Cl 7-Cl 2 NMe ₂ O

9-63 5-Cl 7-Cl 2 Pip O

9-64 5-Cl 7-Cl 2 Mor O

9-65 5-Cl 7-Cl 2 NHMe S

9-66 5-Cl 7-Cl 2 NMe ₂ S

9-67 5-Cl 7-Cl 2 Pip S

9-68 5-Cl 7-Cl 2 Mor S

9-69 4-Br 2 Pip O

9-70 5-Br 2 2 NHMe O

9-71 5-Br 2 NMe ₂ O

9-72 5-Br 2 Pip O

9-73 5-Br 2 Mor O

9-74 6-Br 2 2 NHMe O

9-75 6-Br 2 NMe ₂ O

9-76 6-Br 2 Pip O

9-77 6-Br 2 Mor O

9-78 7-Br 2 2 NHMe O

9-79 7-Br 2 NMe ₂ O

9-80 7-Br 2 Pip O

9-81 7-Br 2 Mor O

9-82 4-Br 6-Cl 2 Pip O

9-83 5-Br 7-Cl 2 Pip O

9-84 4-Me 2 2 NHMe O

9-85 4-Me 2 NMe ₂ O

9-86 4-Me 2 Pip O

9-87 4-Me 2 Mor O

9-88 5-Me 2 2 NHMe O

9-89 5-Me 2 NMe ₂ O

9-90 5-Me 2 Pip O

9-91 5-Me 2 Mor O

9-92 5-Me 2 2 NHMe S

9-93 5-Me 2 NMe ₂ S

9-94 5-Me 2 Pip S

9-95 5-Me 2 Mor S

9-96 6-Me 2 2 NHMe O

9-97 6-Me 2 NMe ₂ O

9-98 6-Me 2 Pip O

9-99 6-Me 2 Mor O

9-100 7-Me 2 2 NHMe O

9-10l 7-Me 2 NMe ₂ O

9-102 7-Me 2 Pip O

9-103 7-Me 2 Mor O

9-104 5-Me 7-Cl 2 2 Pip O

9-105 5-Me 7-Cl 2 2 Pip S

9-106 6-Me 4-Cl 2 2 Pip O

9-107 7-Me 5-Cl 2 2 Pip O

9-108 7-Me 5-Cl 2 2 Pip S

9-109 4-Et 2 Pip O

9-110 4-Et 2 Mor O

9-111 5-Et 2 Pip O

9-112 5-Et 2 Mor O

9-113 6-Et 2 Pip O

9-114 6-Et 2 Mor O

9-115 7-Et 2 Pip O

9-116 7-Et 2 Mor O

9-117 5-Et 7-Cl 2 2 Mor O

9-118 6-Et 4-Cl 2 2 Mor O

9-119 7-Et 5-Cl 2 2 Mor O

9-120 4-OMe 2 NHMe O

9-121 4-OMe 2 NMe ₂ O

9-122 4-OMe 2 Pip O

9-123 4-OMe 2 Mor O

9-124 4-OMe 2 2 NHMe S

9-125 4- _OMe2NMe2S

9-126 4-OMe 2 Pip S

9-127 4-OMe 2 Mor S

9-128 5-OMe 2 2 NHMe O

9-129 5-OMe 2 NMe ₂ O

9-130 5-OMe 2 Pip O

9-131 5-OMe 2 Mor O

9-132 5-OMe 2 2 NHMe S

9-133 5- _OMe2NMe2S

9-134 5-OMe 2 Pip S

9-135 5-OMe 2 Mor S

9-136 6-OMe 2 2 NHMe O

9-137 6-OMe 2 NMe ₂ O

9-138 6-OMe 2 Pip O

9-139 6-OMe 2 Mor O

9-140 7-OMe 2 2 NHMe O

9-141 7-OMe 2 NMe ₂ O

9-142 7-OMe 2 Pip O

9-143 7-OMe 2 2 Mor O

9-144 5-OMe 7-Cl 2 Pip O

9-145 7-OMe 5-Cl 2 Pip O

9-146 4-OEt 2 Pip O

9-147 4-OEt 2 Mor O

9-148 5-OEt 2 Pip O

9-149 5-OEt 2 Mor O

9-150 6-OEt 2 Pip O

9-151 6-OEt 2 2 Mor O

9-152 7-OEt 2 Pip O

9-153 7-OEt 2 2 Mor O

9-154 5-OEt 7-Cl 2 Mor O

9-155 7-OEt 5-Cl 2 mor O

9-156 4-NO2 2 2 NHMe O

9-157 4-NO2 2 NMe ₂ O

9-158 4-NO ₂ 2 Pip O

9-159 4-NO ₂ 2 Mor O

9-160 4-NO ₂ 2 NHMeS

9-161 4-NO ₂ 2 NMe ₂ S

9-162 4-NO ₂ 2 Pip S

9-163 4-NO ₂ 2 Mor S

9-164 5-NO ₂ 2 NHMeO

9-165 5-NO ₂ 2 NMe ₂ O

9-166 5-NO ₂ 2 Pip O

9-167 5-NO ₂ 2 Mor O

9-168 5-NO ₂ 2 NHMeS

9-169 5-NO ₂ 2 NMe ₂ S

9-170 5-NO ₂ 2 Pip S

9-171 5-NO ₂ 2 Mor S

9-172 6-NO ₂ 2 NHMeO

9-173 6-NO ₂ 2 NMKe ₂ O

9-174 6-NO ₂ 2 Pip O

9-175 6-NO ₂ 2 Mor O

9-176 7-NO ₂ 2 NHMeO

9-177 7-NO ₂ 2 NMe ₂ O

9-178 7-NO ₂ 2 Pip O

9-179 7-NO ₂ 2 Mor O

9-180 4-NO ₂ 6-Cl 2 Pip O

9-181 5-NO ₂ 7-Cl 2 Pip O

化合物号       (R¹)_m         n    R² _b X9-182 5-NO ₂ 7-Cl 2 pip S [Table 10]

Compound No. (R ¹ ) _m n R ² _b X

10-1 H H 2 2 NHMe O

10-2 H 2 NMe ₂ O

10-3 H H 2 Pip O

1-4 H H 2 2 Mor O

10-5 H H 2 2 NHMe S

10-6 H 2 NMe ₂ S

10-7 H H 2 2 Pip S

10-8 H H 2 2 Mor S

10-9 4-F 2 NHMe O

10-10 5-F 2 NMe ₂ O

10-11 6-F 2 Pip O

10-12 7-F 2 Mor O

10-13 8-F 2 Pip O

10-14 9-F 2 Mor O

10-15 5-F 2 NMe ₂ S

10-16 6-F 2 Pip S

10-17 7-F 2 Mor S

10-18 8-F 2 Pip S

10-19 5-Cl 2 NMe ₂ O

10-20 6-Cl 2 Pip O

10-21 7-Cl 2 2 Mor O

10-22 8-Cl 2 2 Pip O

10-23 5-Cl 2 NMe ₂ S

10-24 6-Cl 2 Pip S

10-25 7-Cl 2 2 Mor S

10-26 8-C1 2 Pip S

10-27 8-Br 2 Pip O

10-28 5-Br 2 NMe ₂ S

10-29 5-Me 2 NMe ₂ O

10-30 6-Me 2 Pip O

10-31 7-Me 2 Mor O

10-32 8-Me 2 Pip O

10-33 5-Me 2 NMe ₂ S

10-34 6-Me 2 Pip S

10-35 7-Me 2 Mor S

10-36 8-Me 2 Pip S

10-37 8-Et 2 Pip O

10-38 5-Et 2 NMe ₂ S

10-39 5-OMe 2 NMe ₂ O

10-40 6-OMe 2 Pip O

10-41 7-OMe 2 Mor O

10-42 8-OMe 2 Pip O

10-43 5-OMe 2 NMe ₂ S

10-44 6-OMe 2 Pip S

10-45 7-OMe 2 Mor S

10-46 8-OMe 2 Pip S

10-47 8-OEt 2 Pip O

10-48 5-OEt 2 NMe ₂ S

10-49 8-OCHF ₂ 2 Pip O

10-50 5-OCHF ₂ 2 NMe ₂ S

10-51 5-NO ₂ 2 NMe ₂ O

10-52 6-NO ₂ 2 Pip O

10-53 7-NO ₂ 2 Mor O

10-54 8-NO ₂ 2 Pip O

10-55 5-NO ₂ 2 NMe ₂ S

10-56 6-NO ₂ 2 Pip S

10-57 7-NO ₂ 2 Mor S

10-58 8-NO ₂ 2 Pip S

10-59 5-CN 2 NMe ₂ O

10-60 6-CN 2 Pip O

10-61 7-CN 2 2 Mor O

10-62 8-CN 2 Pip O

10-63 5-CN 2 NMe ₂ S

10-64 6-CN 2 Pip S

10-65 7-CN 2 Mor S

化合物号    (R¹)_m           n   R² _b X10-66 8-CN 2 Pip S [Table 11]

Compound No. (R ¹ ) _m n R ² _b X

11-1 H H 2 2 NHMe O

11-2 H 2 NMe ₂ O

11-3 H H 2 Pip O

11-4 H H 2 Mor O

11-5 H H 2 2 NHMe S

11-6 H 2 NMe ₂ S

11-7 H H 2 Pip S

11-8 H H 2 Mor S

11-9 4-F 2 Pip O

11-10 4-F 2 Mor O

11-11 4-F 2 Pip S

11-12 4-F 2 Mor S

11-13 5-F 2 NHMe O

11-14 5-F 2 NMe ₂ O

11-15 5-F 2 Pip O

11-16 5-F 2 Mor O

11-17 5-F 2 2 NHMe S

11-18 5-F 2 NMe ₂ S

11-19 6-F 2 NHMe O

11-20 6-F 2 NMe ₂ O

11-21 6-F 2 Pip O

11-22 6-F 2 Mor O

11-23 4-Cl 2 2 NHMe O

11-24 4-Cl 2 NMe ₂ O

11-25 4-Cl 2 Pip O

11-26 4-Cl 2 2 Mor O

11-27 4-Cl 2 2 NHMe S

11-28 4-Cl 2 NMe ₂ S

11-29 5-Cl 2 2 NHMe O

11-30 5-Cl 2 NMe ₂ O

11-31 5-Cl 2 2 Pip O

11-32 5-Cl 2 2 Mor O

11-33 5-Cl 2 2 NHMe S

11-34 5-Cl 2 NMe ₂ S

11-35 5-Cl 2 pip S

11-36 5-Cl 2 2 Mor S

11-37 6-Cl 2 2 NHMe O

11-38 6-Cl 2 NMe ₂ O

11-39 6-Cl 2 2 Pip O

11-40 6-Cl 2 2 Mor O

11-41 4-Cl 6-Cl 2 NHMe O

11-42 4-Cl 6-Cl 2 NMe ₂ O

11-43 4-Cl 6-Cl 2 Pip O

11-44 4-Br 2 Mor O

11-45 5-Br 2 2 NHMe O

11-46 5-Br 2 NMe ₂ O

11-47 5-Br 2 Pip O

11-48 5-Br 2 Mor O

11-49 5-Br 2 2 NHMe S

11-50 5-Br 2 NMe ₂ S

11-51 6-Br 2 2 NHMe O

11-52 6-Br 2 NMe ₂ O

11-53 6-Br 2 Pip O

11-54 6-Br 2 Mor O

11-55 4-Br 6-Cl 2 Pip O

11-56 4-Me 2 2 NHMe O

11-57 4-Me 2 NMe ₂ O

11-58 4-Me 2 Pip O

11-59 4-Me 2 Mor O

11-60 4-Me 2 NHMe S

11-61 4-Me 2 NMe ₂ S

11-62 4-Me 2 Pip S

11-63 4-Me 2 Mor S

11-64 5-Me 2 NHMe O

11-65 5-Me 2 NMe ₂ O

11-66 5-Me 2 Pip O

11-67 5-Me 2 Mor O

11-68 5-Me 2 2 NHMe S

11-69 5-Me 2 NMe ₂ S

11-70 6-Me 2 2 NHMe O

11-71 6-Me 2 NMe ₂ O

11-72 6-Me 2 Pip O

11-73 6-Me 2 Mor O

11-74 6-Me 4-Cl 2 Pip O

11-75 4-Et 2 Pip O

11-76 4-Et 2 Mor O

11-77 5-Et 2 Pip O

11-78 5-Et 2 Mor O

11-79 5-Et 2 Pip S

11-80 5-Et 2 Mor S

11-81 6-Et 2 Pip O

11-82 6-Et 2 2 Mor O

11-83 6-Et 4-Cl 2 Mor O

11-84 4-OMe 2 2 NHMe O

11-85 4-OMe 2 NMe ₂ O

11-86 4-OMe 2 Pip O

11-87 4-OMe 2 Mor O

11-88 4-OMe 2 2 NHMe S

11-89 4-OMe 2 NMe ₂ S

11-90 4-OMe 2 Pip S

11-91 4-OMe 2 Mor S

11-92 5-OMe 2 2 NHMe O

11-93 5-OMe 2 NMe ₂ O

11-94 5-OMe 2 Pip O

11-95 5-OMe 2 Mor O

11-96 5-OMe 2 2 NHMe S

11-97 5-OMe 2 NMe ₂ S

11-98 5-OMe 2 Pip S

11-99 5-OMe 2 Mor S

11-100 6-OMe 2 2 NHMe O

11-101 6-OMe 2 NMe ₂ O

11-102 6-OMe 2 Pip O

11-103 6-OMe 2 Mor O

11-104 4-OEt 2 Pip O

11-105 4-OEt 2 Mor O

11-106 4-OEt 2 Pip S

11-107 4-OEt 2 Mor S

11-108 5-OEt 2 Pip O

11-109 5-OEt 2 Mor O

11-110 5-OEt 2 Pip S

11-111 5-OEt 2 Mor S

11-112 6-OEt 2 Pip O

11-113 6-OEt 2 Mor O

11-114 4-NO ₂ 2 NHMeO

11-115 4-NO ₂ 2 NMe ₂ O

11-116 4-NO ₂ 2 Pip O

11-117 4-NO ₂ 2 Mor O

11-118 4-NO ₂ 2 NHMeS

11-119 4-NO ₂ 2 NMe ₂ S

11-120 4-NO ₂ 2 Pip S

11-121 4-NO ₂ 2 Mor S

11-122 5-NO ₂ 2 NHMeO

11-123 5-NO ₂ 2 NMe ₂ O

11-124 5-NO ₂ 2 Pip O

11-125 5-NO ₂ 2 Mor O

11-126 5-NO ₂ 2 NHMeS

11-127 5-NO ₂ 2 NMe ₂ S

11-128 5-NO ₂ 2 Pip S

11-129 5-NO ₂ 2 Mor S

11-130 6-NO ₂ 2 NHMeO

11-131 6-NO ₂ 2 NMe ₂ O

11-132 6-NO ₂ 2 Pip O

11-133 6-NO ₂ 2 Mor O

化合物号      (R¹)_m           n    R² _b X11-134 4-NO ₂ 6-Cl 2 Pip O [Table 12]

Compound No. (R ¹ ) _m n R ² _b X

12-1 H H 2 2 NHMe O

_12-2H2NMe2O

12-3 H H 2 2 Pip O

12-4 H H 2 2 Mor O

12-5 H H 2 2 NHMe S

12-6 H 2 NMe ₂ S

12-7 H H 2 Pip S

12-8 H H 2 2 Mor S

12-9 7-F 2 Pip O

12-10 7-F 2 2 Mor O

12-11 7-F 2 Pip S

12-12 7-F 2 2 Mor S

12-13 5-F 2 NHMe O

12-14 5-F 2 NMe ₂ O

12-15 5-F 2 Pip O

12-16 5-F 2 2 Mor O

12-17 5-F 2 2 NHMe S

12-18 5-F 2 NMe ₂ S

12-19 6-F 2 2 NHMe O

12-20 6-F 2 NMe ₂ O

12-21 6-F 2 Pip O

12-22 6-F 2 Mor O

12-23 7-Cl 2 2 NHMe O

12-24 7-Cl 2 NMe ₂ O

12-25 7-Cl 2 Pip O

12-26 7-Cl 2 2 Mor O

12-27 7-Cl 2 2 NHMe S

12-28 7-Cl 2 NMe ₂ S

12-29 5-Cl 2 2 NHMe O

12-30 5-Cl 2 NMe ₂ O

12-31 5-Cl 2 Pip O

12-32 5-Cl 2 2 Mor O

12-33 5-Cl 2 2 NHMe S

12-34 5-Cl 2 NMe ₂ S

12-35 5-Cl 2 Pip S

12-36 5-Cl 2 2 Mor S

12-37 6-Cl 2 2 NHMe O

12-38 6-Cl 2 NMe ₂ O

12-39 6-Cl 2 2 Pip O

12-40 6-Cl 2 2 Mor O

12-41 7-Cl 6-Cl 2 NHMe O

12-42 7-Cl 6-Cl 2 NMe ₂ O

12-43 7-Cl 6-Cl 2 Pip O

12-44 7-Br 2 Mor O

12-45 5-Br 2 2 NHMe O

12-46 5-Br 2 NMe ₂ O

12-47 5-Br 2 Pip O

12-48 5-Br 2 Mor O

12-49 5-Br 2 2 NHMe S

12-50 5-Br 2 NMe ₂ S

12-51 6-Br 2 2 NHMe O

12-52 6-Br 2 NMe ₂ O

12-53 6-Br 2 Pip O

12-54 6-Br 2 Mor O

12-55 7-Br 6-Cl 2 Pip O

12-56 7-Me 2 2 NHMe O

12-57 7-Me 2 NMe ₂ O

12-58 7-Me 2 Pip O

12-59 7-Me 2 Mor O

12-60 7-Me 2 NHMe S

12-61 7-Me 2 NMe ₂ S

12-62 7-Me 2 Pip S

12-63 7-Me 2 Mor S

12-64 5-Me 2 2 NHMe O

12-65 5-Me 2 NMe ₂ O

12-66 5-Me 2 Pip O

12-67 5-Me 2 Mor O

12-68 5-Me 2 NHMe S

12-69 5-Me 2 NMe ₂ S

12-70 6-Me 2 2 NHMe O

12-71 6-Me 2 NMe ₂ O

12-72 6-Me 2 Pip O

12-73 6-Me 2 Mor O

12-74 6-Me 7-Cl 2 Pip O

12-75 7-Et 2 Pip O

12-76 7-Et 2 Mor O

12-77 5-Et 2 Pip O

12-78 5-Et 2 Mor O

12-79 5-Et 2 Pip S

12-80 5-Et 2 Mor S

12-81 6-Et 2 Pip O

12-82 6-Et 2 Mor O

12-83 6-Et 7-Cl 2 Mor O

12-84 7-OMe 2 2 NHMe O

12-85 7-OMe 2 NMe ₂ O

12-86 7-OMe 2 Pip O

12-87 7-OMe 2 Mor O

12-88 7-OMe 2 2 NHMe S

12-89 7-OMe 2 NMe ₂ S

12-90 7-OMe 2 Pip S

12-91 7-OMe 2 Mor S

12-92 5-OMe 2 2 NHMe O

12-93 5-OMe 2 NMe ₂ O

12-94 5-OMe 2 Pip O

12-95 5-OMe 2 Mor O

12-96 5-OMe 2 NHMe S

12-97 5-OMe 2 NMe ₂ S

12-98 5-OMe 2 Pip S

12-99 5-OMe 2 Mor S

12-100 6-OMe 2 2 NHMe O

12-101 6-OMe 2 NMe ₂ O

12-102 6-OMe 2 Pip O

12-103 6-OMe 2 Mor O

12-104 7-OEt 2 Pip O

12-105 7-OEt 2 Mor O

12-106 7-OEt 2 Pip S

12-107 7-OEt 2 Mor S

12-108 5-OEt 2 Pip O

12-109 5-OEt 2 Mor O

12-110 5-OEt 2 Pip S

12-111 5-OEt 2 Mor S

12-112 6-OEt 2 Pip O

12-113 6-OEt 2 Mor O

12-114 7-NO ₂ 2 NHMeO

12-115 7-NO ₂ 2 NMe ₂ O

12-116 7-NO ₂ 2 Pip O

12-117 7-NO ₂ 2 Mor O

12-118 7-NO ₂ 2 NHMe S

12-119 7-NO ₂ 2 NMe ₂ S

12-120 7-NO ₂ 2 Pip S

12-121 7-NO ₂ 2 Mor S

12-122 5-NO ₂ 2 NHMeO

12-123 5-NO ₂ 2 NMe ₂ O

12-124 5-NO ₂ 2 Pip O

12-125 5-NO ₂ 2 Mor O

12-126 5-NO ₂ 2 NHMeS

12-127 5-NO ₂ 2 NMe ₂ S

12-128 5-NO ₂ 2 Pip S

12-129 5-NO ₂ 2 Mor S

12-130 6-NO ₂ 2 NHMeO

12-131 6-NO ₂ 2 NMe ₂ O

12-132 6-NO ₂ 2 Pip O

12-133 6-NO ₂ 2 Mor O

12-134 7-NO ₂ 6-Cl 2 Pip O [Table 13] Compound No. (R ¹ ) _m n R ² _b X

13-1 H H 2 2 NHMe O

13-2 H 2 NMe ₂ O

13-3 H H 2 Pip O

13-4 H H 2 Mor O

13-5 H H 2 2 NHMe S

13-6 H 2 NMe ₂ S

13-7 H H 2 Pip S

13-8 H H 2 Mor S

13-9 7-F 2 Pip O

13-10 7-F 2 Mor O

13-11 7-F 2 Pip S

13-12 7-F 2 Mor S

13-13 4-F 2 NHMe O

13-14 4-F 2 NMe ₂ O

13-15 4-F 2 Pip O

13-16 4-F 2 Mor O

13-17 4-F 2 NHMe S

13-18 4-F 2 NMe ₂ S

13-19 6-F 2 NHMe O

13-20 6-F 2 NMe ₂ O

13-21 6-F 2 Pip O

13-22 6-F 2 Mor O

13-23 7-C1 2 2 NHMe O

13-24 7-Cl 2 NMe ₂ O

13-25 7-Cl 2 2 Pip O

13-26 7-Cl 2 2 Mor O

13-27 7-Cl 2 2 NHMe S

13-28 7-Cl 2 NMe ₂ S

13-29 4-Cl 2 2 NHMe O

13-30 4-Cl 2 NMe ₂ O

13-31 4-Cl 2 2 Pip O

13-32 4-Cl 2 2 Mor O

13-33 4-Cl 2 2 NHMe S

13-34 4-Cl 2 NMe ₂ S

13-35 4-Cl 2 Pip S

13-36 4-Cl 2 2 Mor S

13-37 6-Cl 2 2 NHMe O

13-38 6-Cl 2 NMe ₂ O

13-39 6-Cl 2 2 Pip O

13-40 6-Cl 2 2 Mor O

13-41 7-Cl 6-Cl 2 NHMe O

13-42 7-Cl 6-Cl 2 NMe ₂ O

13-43 7-Cl 6-Cl 2 Pip O

13-44 7-Br 2 Mor O

13-45 4-Br 2 2 NHMe O

13-46 4-Br 2 NMe ₂ O

13-47 4-Br 2 Pip O

13-48 4-Br 2 Mor O

13-49 4-Br 2 2 NHMe S

13-50 4-Br 2 NMe ₂ S

13-51 6-Br 2 2 NHMe O

13-52 6-Br 2 NMe ₂ O

13-53 6-Br 2 Pip O

13-54 6-Br 2 Mor O

13-55 7-Br 6-Cl 2 Pip O

13-56 7-Me 2 2 NHMe O

13-57 7-Me 2 NMe ₂ O

13-58 7-Me 2 Pip O

13-59 7-Me 2 Mor O

13-60 7-Me 2 2 NHMe S

13-61 7-Me 2 NMe ₂ S

13-62 7-Me 2 Pip S

13-63 7-Me 2 Mor S

13-64 4-Me 2 2 NHMe O

13-65 4-Me 2 NMe ₂ O

13-66 4-Me 2 Pip O

13-67 4-Me 2 Mor O

13-68 4-Me 2 2 NHMe S

13-69 4-Me 2 NMe ₂ S

13-70 6-Me 2 2 NHMe O

13-71 6-Me 2 NMe ₂ O

13-72 6-Me 2 Pip O

13-73 6-Me 2 Mor O

13-74 6-Me 7-Cl 2 Pip O

13-75 7-Et 2 Pip O

13-76 7-Et 2 Mor O

13-77 4-Et 2 Pip O

13-78 4-Et 2 Mor O

13-79 4-Et 2 Pip S

13-80 4-Et 2 Mor S

13-81 6-Et 2 Pip O

13-82 6-Et 2 2 Mor O

13-83 6-Et 7-Cl 2 Mor O

13-84 7-OMe 2 2 NHMe O

13-85 7-OMe 2 NMe ₂ O

13-86 7-OMe 2 Pip O

13-87 7-OMe 2 Mor O

13-88 7-OMe 2 2 NHMe S

13-89 7-OMe 2 NMe ₂ S

13-90 7-OMe 2 Pip S

13-91 7-OMe 2 Mor S

13-92 4-OMe 2 2 NHMe O

13-93 4-OMe 2 NMe ₂ O

13-94 4-OMe 2 Pip O

13-95 4-OMe 2 Mor O

13-96 4-OMe 2 2 NHMe S

13-97 4-OMe 2 NMe ₂ S

13-98 4-OMe 2 Pip S

13-99 4-OMe 2 Mor S

13-100 6-OMe 2 2 NHMe O

13-101 6-OMe 2 NMe ₂ O

13-102 6-OMe 2 Pip O

13-103 6-OMe 2 Mor O

13-104 7-OEt 2 Pip O

13-105 7-OEt 2 Mor O

13-106 7-OEt 2 Pip S

13-107 7-OEt 2 Mor S

13-108 4-OEt 2 Pip O

13-109 4-OEt 2 Mor O

13-110 4-OEt 2 Pip S

13-111 4-OEt 2 Mor S

13-112 6-OEt 2 Pip O

13-113 6-OEt 2 Mor O

13-114 7-NO ₂ 2 NHMeO

13-115 7-NO ₂ 2 NMe ₂ O

13-116 7-NO ₂ 2 Pip O

13-117 7-NO ₂ 2 Mor O

13-118 7-NO ₂ 2 NHMeS

13-119 7-NO ₂ 2 NMe ₂ S

13-120 7-NO ₂ 2 Pip S

13-121 7-NO ₂ 2 Mor S

13-122 4-NO ₂ 2 NHMeO

13-123 4-NO ₂ 2 NMe ₂ O

13-124 4-NO ₂ 2 Pip O

13-125 4-NO ₂ 2 Mor O

13-126 4-NO ₂ 2 NHMeS

13-127 4-NO ₂ 2 NMe ₂ S

13-128 4-NO ₂ 2 Pip S

13-129 4-NO ₂ 2 Mor S

13-130 6-NO ₂ 2 NHMeO

13-131 6-NO ₂ 2 NMe ₂ O

13-132 6-NO ₂ 2 Pip O

13-133 6-NO ₂ 2 Mor O

13-134 7-NO ₂ 6-Cl 2 pip O [Table 14] Compound No. (R ¹ ) _m n R ² _b X

14-1 H H 2 NHMe O

14-2 H 2 NMe ₂ O

14-3 H H 2 Pip O

14-4 H H 2 Mor O

14-5 H H 2 NHMe S

14-6 H 2 NMe ₂ S

14-7 H H 2 Pip S

14-8 H H 2 Mor S

14-9 7-F 2 Pip O

14-10 7-F 2 Mor O

14-11 7-F 2 Pip S

14-12 7-F 2 Mor S

14-13 4-F 2 NHMe O

14-14 4-F 2 NMe ₂ O

14-15 4-F 2 Pip O

14-16 4-F 2 Mor O

14-17 4-F 2 NHMe S

14-18 4-F 2 NMe ₂ S

14-19 5-F 2 NHMe O

14-20 5-F 2 NMe ₂ O

14-21 5-F 2 Pip O

14-22 5-F 2 Mor O

14-23 7-C1 2 2 NHMe O

14-24 7-Cl 2 NMe ₂ O

14-25 7-Cl 2 Pip O

14-26 7-Cl 2 2 Mor O

14-27 7-Cl 2 2 NHMe S

14-28 7-Cl 2 NMe ₂ S

14-29 4-Cl 2 2 NHMe O

14-30 4-Cl 2 NMe ₂ O

14-31 4-Cl 2 Pip O

14-32 4-Cl 2 2 Mor O

14-33 4-Cl 2 2 NHMe S

14-34 4-Cl 2 NMe ₂ S

14-35 4-Cl 2 Pip S

14-36 4-Cl 2 Mor S

14-37 5-Cl 2 2 NHMe O

14-38 5-Cl 2 NMe ₂ O

14-39 5-Cl 2 Pip O

14-40 5-Cl 2 2 Mor O

14-41 7-Cl 5-Cl 2 NHMe O

14-42 7-Cl 5-Cl 2 NMe ₂ O

14-43 7-Cl 5-Cl 2 Pip O

14-44 7-Br 2 Mor O

14-45 4-Br 2 2 NHMe O

14-46 4-Br 2 NMe ₂ O

14-47 4-Br 2 Pip O

14-48 4-Br 2 Mor O

14-49 4-Br 2 2 NHMe S

14-50 4-Br 2 NMe ₂ S

14-51 5-Br 2 2 NHMe O

14-52 5-Br 2 NMe ₂ O

14-53 5-Br 2 Pip O

14-54 5-Br 2 Mor O

14-55 7-Br 5-Cl 2 Pip O

14-56 7-Me 2 NHMe O

14-57 7-Me 2 NMe ₂ O

14-58 7-Me 2 Pip O

14-59 7-Me 2 Mor O

14-60 7-Me 2 NHMe S

14-61 7-Me 2 NMe ₂ S

14-62 7-Me 2 Pip S

14-63 7-Me 2 Mor S

14-64 4-Me 2 NHMe O

14-65 4-Me 2 NMe ₂ O

14-66 4-Me 2 Pip O

14-67 4-Me 2 Mor O

14-68 4-Me 2 NHMe S

14-69 4-Me 2 NMe ₂ S

14-70 5-Me 2 NHMe O

14-71 5-Me 2 NMe ₂ O

14-72 5-Me 2 Pip O

14-73 5-Me 2 Mor O

14-74 5-Me 7-Cl 2 Pip O

14-75 7-Et 2 Pip O

14-76 7-Et 2 Mor O

14-77 4-Et 2 Pip O

14-78 4-Et 2 Mor O

14-79 4-Et 2 Pip S

14-80 4-Et 2 Mor S

14-81 5-Et 2 Pip O

14-82 5-Et 2 Mor O

14-83 5-Et 7-Cl 2 2 Mor O

14-84 7-OMe 2 2 NHMe O

14-85 7-OMe 2 NMe ₂ O

14-86 7-OMe 2 Pip O

14-87 7-OMe 2 Mor O

14-88 7-OMe 2 2 NHMe S

14-89 7-OMe 2 NMe ₂ S

14-90 7-OMe 2 Pip S

14-91 7-OMe 2 Mor S

14-92 4-OMe 2 2 NHMe O

14-93 4-OMe 2 NMe ₂ O

14-94 4-OMe 2 Pip O

14-95 4-OMe 2 Mor O

14-96 4-OMe 2 2 NHMe S

14-97 4-OMe 2 NMe ₂ S

14-98 4-OMe 2 Pip S

14-99 4-OMe 2 Mor S

14-100 5-OMe 2 2 NHMe O

14-101 5-OMe 2 NMe ₂ O

14-102 5-OMe 2 Pip O

14-103 5-OMe 2 Mor O

14-104 7-OEt 2 Pip O

14-105 7-OEt 2 Mor O

14-106 7-OEt 2 Pip S

14-107 7-OEt 2 Mor S

14-108 4-OEt 2 pip O

14-109 4-OEt 2 Mor O

14-110 4-OEt 2 Pip S

14-111 4-OEt 2 Mor S

14-112 5-OEt 2 Pip O

14-113 5-OEt 2 Mor O

14-114 7-NO ₂ 2 NHMeO

14-115 7-NO ₂ 2 NMe ₂ O

14-116 7-NO ₂ 2 Pip O

14-117 7-NO ₂ 2 Mor O

14-118 7-NO ₂ 2 NHMeS

14-119 7-NO ₂ 2 NMe ₂ S

14-120 7-NO ₂ 2 Pip S

14-121 7-NO ₂ 2 Mor S

14-122 4-NO ₂ 2 NHMeO

14-123 4-NO ₂ 2 NMe ₂ O

14-124 4-NO ₂ 2 Pip O

14-125 4-NO ₂ 2 Mor O

14-126 4-NO ₂ 2 NHMeS

14-127 4-NO ₂ 2 NMe ₂ S

14-128 4-NO ₂ 2 Pip S

14-129 4-NO ₂ 2 Mor S

14-130 5-NO ₂ 2 NHMeO

14-131 5-NO ₂ 2 NMe ₂ O

14-132 5-NO ₂ 2 Pip O

14-133 5-NO ₂ 2 Mor O

14-134 7-NO ₂ 5-Cl 2 Pip O [Table 15] Compound No. (R ¹ ) _m n R ² _b X

15-1 H H 2 2 NHMe O

15-2 H 2 NMe ₂ O

15-3 H H 2 Pip O

15-4 H H 2 Mor O

15-5 H H 2 2 NHMe S

15-6 H 2 NMe ₂ S

15-7 H H 2 Pip S

15-8 H H 2 Mor S

15-9 5-F 2 2 NHMe O

15-10 5-F 2 NMe ₂ O

15-11 5-F 2 Pip O

15-12 5-F 2 Mor O

15-13 6-F 2 2 NHMe O

15-14 6-F 2 NMe ₂ O

15-15 6-F 2 Pip O

15-16 6-F 2 Mor O

15-17 6-F 2 2 NHMe S

15-18 6-F 2 NMe ₂ S

15-19 6-F 2 Pip S

15-20 6-F 2 Mor S

15-21 5-Cl 2 2 NHMe O

15-22 5-Cl 2 NMe ₂ O

15-23 5-Cl 2 2 Pip O

15-24 5-Cl 2 2 Mor O

15-25 6-Cl 2 2 NHMe O

15-26 6-Cl 2 NMe ₂ O

15-27 6-Cl 2 2 Pip O

15-28 6-Cl 2 2 Mor O

15-29 6-Cl 2 2 NHMe S

15-30 6-Cl 2 NMe ₂ S

15-31 6-Cl 2 2 Pip S

15-32 6-Cl 2 2 Mor S

15-33 5-Br 2 Mor O

15-34 6-Br 2 2 NHMe O

15-35 6-Br 2 NMe ₂ O

15-36 6-Br 2 Pip O

15-37 6-Br 2 Mor O

15-38 5-Me 2 2 NHMe O

15-39 5-Me 2 NMe ₂ O

15-40 5-Me 2 Pip O

15-41 5-Me 2 Mor O

15-42 6-Me 2 2 NHMe O

15-43 6-Me 2 NMe ₂ O

15-44 6-Me 2 Pip O

15-45 6-Me 2 Mor O

15-46 6-Me 2 2 NHMe S

15-47 6-Me 2 NMe ₂ S

15-48 6-Me 2 Pip S

15-49 6-Me 2 Mor S

15-50 5-Et 2 Pip O

15-51 5-Et 2 Mor O

15-52 6-Et 2 Pip O

15-53 6-Et 2 2 Mor O

15-54 5-MeO 2 2 NHMe O

15-55 5-MeO 2 NMe ₂ O

15-56 5-MeO 2 Pip O

15-57 5-MeO 2 2 Mor O

15-58 6-MeO 2 2 NHMe O

15-59 6-MeO 2 NMe ₂ O

15-60 6-MeO 2 Pip O

15-61 6-MeO 2 2 Mor O

15-62 6-MeO 2 2 NHMe S

15-63 6-MeO 2 NMe ₂ S

15-64 6-MeO 2 Pip S

15-65 6-MeO 2 2 Mor S

15-66 5-EtO 2 Pip O

15-67 5-EtO 2 Mor O

15-68 6-EtO 2 Pip O

15-69 6-EtO 2 Mor O

15-70 5-NO ₂ 2 NHMeO

15-71 5-NO ₂ 2 NMe ₂ O

15-72 5-NO ₂ 2 Pip O

15-73 5-NO ₂ 2 Mor O

15-74 6-NO ₂ 2 NHMeO

15-75 6-NO ₂ 2 NMe ₂ O

15-76 6-NO ₂ 2 Pip O

15-77 6-NO ₂ 2 Mor O

15-78 6-NO ₂ 2 NHMe S

15-79 6-NO ₂ 2 NMe ₂ S

15-80 6-NO ₂ 2 Pip S

15-81 6-NO ₂ 2 Mor S [Table 16] Compound No. (R ¹ ) _m n R ² _b X

16-1 H H 2 NHMe O

16-2 H 2 NMe ₂ O

16-3 H H 2 Pip O

16-4 H H 2 Mor O

16-5 H H 2 NHMe S

16-6 H 2 NMe ₂ S

16-7 H H 2 Pip S

16-8 H H 2 Mor S

16-9 4-F 2 Pip O

16-10 4-F 2 Mor O

16-11 4-F 2 Pip S

16-12 4-F 2 Mpr S

16-13 5-F 2 NHMe O

16-14 5-F 2 NMe ₂ O

16-15 5-F 2 Pip O

16-16 5-F 2 Mor O

16-17 4-Cl 2 2 NHMe O

16-18 4-Cl 2 NMe ₂ O

16-19 4-Cl 2 Pip O

16-20 4-Cl 2 Mor O

16-21 4-Cl 2 2 NHMe S

16-22 4-Cl 2 NMe ₂ S

16-23 4-C1 2 Pip S

16-24 4-Cl 2 2 Mor S

16-25 5-Cl 2 2 NHMe O

16-26 5-Cl 2 NMe ₂ O

16-27 5-Cl 2 2 Pip O

16-28 5-Cl 2 2 Mor O

16-29 4-Br 2 2 NHMe O

16-30 4-Br 2 NMe ₂ O

16-31 4-Br 2 Pip O

16-32 5-Br 2 2 Mor O

16-33 4-Me 2 2 NHMe O

16-34 4-Me 2 NMe ₂ O

16-35 4-Me 2 Pip O

16-36 4-Me 2 Mor O

16-37 4-Me 2 2 NHMe S

16-38 4-Me 2 NMe ₂ S

16-39 4-Me 2 Pip S

16-40 4-Me 2 Mor S

16-41 5-Me 2 2 NHMe O

16-42 5-Me 2 NMe ₂ O

16-43 5-Me 2 Pip O

16-44 5-Me 2 Mor O

16-45 4-Et 2 Pip O

16-46 4-Et 2 Mor O

16-47 5-Et 2 Pip O

16-48 5-Et 2 2 Mor O

16-49 4-MeO 2 NHMe O

16-50 4-MeO 2 NMe ₂ O

16-51 4-MeO 2 Pip O

16-52 4-MeO 2 Mor O

16-53 4-MeO 2 2 NHMe S

16-54 4-MeO 2 NMe ₂ S

16-55 4-MeO 2 Pip S

16-56 4-MeO 2 2 Mor S

16-57 5-MeO 2 2 NHMe O

16-58 5-MeO 2 NMe ₂ O

16-59 5-MeO 2 Pip O

16-60 5-MeO 2 Mor O

16-61 4-EtO 2 Pip O

16-62 4-EtO 2 Mor O

16-63 5-EtO 2 Pip O

16-64 5-EtO 2 Mor O

16-65 4-NO ₂ 2 NHMeO

16-66 4-NO ₂ 2 NMe ₂ O

16-67 4-NO ₂ 2 pip O

16-68 4-NO ₂ 2 Mor O

16-69 4-NO ₂ 2 NHMeS

16-70 4-NO ₂ 2 NMe ₂ S

16-71 4-NO ₂ 2 Pip S

16-72 4-NO ₂ 2 Mor S

16-73 5-NO ₂ 2 NHMeO

16-74 5-NO ₂ 2 NMe ₂ O

16-75 5-NO ₂ 2 Pip O

16-76 5-NO ₂ 2 Mor O

The following compounds can be given as suitable isoxazole derivatives of general formula (I) according to the invention [formulas (Ia), (Ib), (Ic), (Id) and (Ie)]: 1-3, 1 -13, 1-15, 1-19, 1-22, 1-25, 1-28, 1-31, 1-38, 1-41, 1-44, 1-47, 1-

48, 1-49, 1-50, 1-51, 1-53, 1-56, 1-59, 1-60, 1-62, 1-66, 1-68, 1-69, 1-72, 1-75, 1-76,

1-85, 1-96, 1-97, 1-98, 1-107, 1-119, 1-122, 1-125, 1-126, 1-128, 1-135, 1-142, 1- 148,

1-151, 1-160, 1-168, 1-169, 1-170, 1-173, 1-176, 1-185, 1-186, 1-191, 1-193, 1-197, 1-

198, 1-199, 1-200, 1-204, 1-207, 1-216, 1-217, 1-218, 1-219, 1-220, 1-221, 1-224, 1-

23 1, 1-240, 1-241, 1-242, 1-243, 1-244, 1-247, 1-263, 1-264, t-265, 1-266, 1-267, 1-

268, 1-269, 1-272, 1-275, 1-277, 1-278, 1-281, 1-283, 1-284, 1-285, 1-286, 1-287, 1-

291, 1-292, 1-293, 1-294, 1-310, 1-311, 1-312, 1-328, 1-346, 1-362, 1-363, 1-364, 1-

365, 1-381, 1-384, 1-400, 1-401, 1-402, 1-403, 1-404, 1-405, 1-406, 1-414, 1-421, 1-

422, 1-423, 1-429, 1-435, 1-438, 1-439, 1-440, 1-441, 1-442, 1-448, 1-457, 1-460, 1-

461, 1-462, 1-463, 1-464, 1-465, 1-471, 1-473, 1-474, 1-480, 1-481, 1-482, 1-490, 1-

497, 1-498, 1-499, 1-500, 1-501, 1-502, 1-518, 1-519, 1-520, 1-521, 1-528, 1-534, 1-537, 1-

550, 1-553, 1-554, 1-555, 1-556, 1-572, 1-573, 1-574, 1-575, 1-576, 1-577, 1-578, 1-

579, 1-580, 1-581, 1-582, 1-583, 1-586, 1-594, 1-596, 1-598, 1-618, 2-3, 2-53, 3-2, 3-

3, 3-18, 3-19, 3-41, 3-83, 4-2, 4-3, 5-2, 5-3, 6-2 or 6-3

More preferred are compounds 1-3, 1-1 3, 1-1 5, 1-22, 1-

28, 1-31, 1-38, 1-44, 1-51, 1-53, 1-59, 1-60, 1-62, 1-68, 1-69, 1-75, 1-76, 1-85, 1-97,

1-98, 1-107, 1-119, 1-126, 1-128, 1-142, 1-148, 1-151, 1-160, 1-169, 1-170, 1-173, 1-

176, 1-191, 1-193, 1-197, 1-200, 1-207, 1-224, 1-247, 1-269, 1-275, 1-277, 1-293, 1-

294, 1-312, 1-328, 1-346, 1-365, 1-384, 1-405, 1-406, 1-414, 1-422, 1-441, 1-464, 1-

473, 1-480, 1-481, 1-482, 1-490, 1-498, 1-502, 1-521, 1-537, 1-556, 1-572, 1-574, 1-

580, 1-581, 1-583, 1-586, 1-594, 1-596, 1-598, 1-618, 2-3, 3-2, 3-18, 3-19, 3-41, 3-83

or 4-2

Particularly preferred are the following compounds: Compound 1-3: 3-(2-aminoethoxy)-1,2-benzisoxazole, Compound 1-15: 3-(2-aminoethoxy)-5 -Fluoro-1,2-benzisoxazole, compound 1-22: 3-(2-aminoethoxy)-5-fluoro-4-methyl-1,2-benzisoxazole, compound 1 -31: 3-(2-aminoethylthio)-5-fluoro-1,2-benzisoxazole, compound 1-53: 3-(2-aminoethoxy)-5-chloro-1, 2-Benzisoxazole, compound 1-59: 3-(2-aminoethoxy)-5,7-dichloro-1,2-benzisoxazole, compound 1-62: 3-(2 -aminoethylthio)-5-chloro-7-methyl-1,2-benzisoxazole, compound 1-69: 3-(2-aminoethylthio)-5-chloro-1,2- Benzisoxazole, compound 1-85: 3-(2-aminoethoxy)-6-chloro-1,2-benzisoxazole, compound 1-97: 3-(2-aminoethoxy )-7-chloro-1,2-benzisoxazole, compound 1-119: 3-(2-aminoethoxy)-5-bromo-1,2-benzisoxazole, compound 1-142 : 3-(2-aminoethoxy)-5-methyl-1,2-benzisoxazole, compound 1-151: 3-(2-aminoethylthio)-5-methyl-1, 2-Benzisoxazole, compound 1-160: 3-(2-aminoethoxy)-6-methyl-1,2-benzisoxazole, compound 1-169: 3-(2-amino Ethoxy)-7-methyl-1,2-benzisoxazole, compound 1-193: 3-(2-aminoethoxy)-5-methoxy-1,2-benzisoxazole Azole, compound 1-197: 3-(2-aminoethylthio)-5-methoxy-1,2-benzisoxazole, compound 1-224: 3-(2-aminoethoxy)- 5-Difluoromethoxy-1,2-benzisoxazole, compound 1-269: 3-(2-aminoethoxy)-5-fluoro-4-methylthio-1,2-benzo Isoxazole, compound 1-422: 3-(2-aminoethoxy)-5-methoxycarbonyl-1,2-benzisoxazole, compound 1-521: 3-(2-aminoethoxy )-5-nitro-1,2-benzisoxazole, compound 1-537: 3-(2-aminoethylthio)-5-nitro-1,2-benzisoxazole, compound 1 -572: 3-(2-aminoethoxy)-4-cyano-1,2-benzisoxazole, or compound 3-2: 3-(2-aminoethoxy)pyrido[3, 2-d] isoxazole.

The following compounds can be given as suitable isoxazole derivatives represented by the general formula (II) of the present invention [formula (Ia), (Ib), (Ic), (Id) , (Ie), (IIa), (IIb), (IIc), (IId) or (IIe)]: 1-3, 1-13, 1-15, 1-19, 1-22, 1-25, 1-28, 1-31, 1-38, 1-41, 1-44, 1-47, 1-48, 1-49, 1-50, 1-51, 1-53, 1-56, 1- 59, 1-60, 1-62, 1-66, 1-68, 1-69, 1-72, 1-75, 1-76, 1-85, 1-96, 1-97, 1-98, 1-107, 1-119, 1-122, 1-125, 1-126, 1-128, 1-135, 1-142, 1-148, 1-151, 1-160, 1-168, 1- 169, 1-170, 1-173, 1-176, 1-185, 1-186, 1-191, 1-193, 1-197, 1-198, 1-199, 1-200, 1-204, 1-207, 1-216, 1-217, 1-218, 1-219, 1-220, 1-221, 1-224, 1-231, 1-240, 1-241, 1-242, 1- 243, 1-244, 1-247, 1-263, 1-264, 1-265, 1-266, 1-267, 1-268, 1-269, 1-272, 1-275, 1-277, 1-278, 1-281, 1-283, 1-284, 1-285, 1-286, 1-287, 1-291, 1-292, 1-293, 1-294, 1-310, 1- 311, 1-312, 1-328, 1-346, 1-362, 1-363, 1-364, 1-365, 1-381, 1-384, 1-400, 1-401, 1-402, 1-403, 1-404, 1-405, 1-406, 1-414, 1-421, 1-422, 1-423, 1-429, 1-435, 1-438, 1-439, 1- 440, 1-441, 1-442, 1-448, 1-457, 1-460, 1-461, 1-462, 1-463, 1-464, 1-465, 1-471, 1-473, 1-474, 1-480, 1-481, 1-482, 1-490, 1-497, 1-498, 1-499, 1-500, 1-501, 1-502, 1-518, 1- 519, 1-520, 1-521, 1-528, 1-534, 1-

537, 1-550, 1-553, 1-554, 1-555, 1-556, 1-572, 1-573, 1-5 74, 1-575, 1-576, 1-577, 1-

578, 1-579, 1-580, 1-581, 1-582, 1-583, 1-586, 1-594, 1-596, 1-598, 1-618, 2-3, 2-53,

3-2, 3-3, 3-18, 3-19, 4-2, 4-3, 5-2, 5-3, 6-2, 6-3, 9-1, 9-2, 9- 5, 9-6, 10-1, 10-2, 10-5,

10-6, 11-1, 11-2, 11-5, 11-6, 12-1, 12-2, 12-5, 12-6, 13-1, 13-2, 13-5, 13- 6, 14-1, 14-2,

14-5, 14-6, 15-1, 15-2, 15-5, 15-6, 16-1, 16-2, 16-5 or 16-6

More preferred are compounds 1-3, 1-1 3, 1-1 5, 1-22, 1-28, 1-3 1, 1-

44, 1-51, 1-53, 1-59, 1-60, 1-62, 1-68, 1-69, 1-75, 1-76, 1-85, 1-97, 1-98, 1-107, 1-

119, 1-126, 1-128, 1-142, 1-148, 1-151, 1-160, 1-169, 1-170, 1-173, 1-176, 1-191, 1-

193, 1-197, 1-200, 1-207, 1-224, 1-247, 1-269, 1-275, 1-277, 1-293, 1-294, 1-312, 1-

328, 1-346, 1-365, 1-384, 1-405, 1-406, 1-414, 1-422, 1-441, 1-464, 1-473, 1-480, 1-

481, 1-482, 1-490, 1-498, 1-502, 1-521, 1-537, 1-556, 1-572, 1-574, 1-580, 1-581, 1-

583, 1-586, 1-594, 1-596, 1-598, 1-618, 2-3, 3-2, 3-18, 3-19, 3-41, 3-83 or 4-2

Particularly preferred are the following compounds: Compound 1-3: 3-(2-aminoethoxy)-1,2-benzisoxazole, Compound 1-15: 3-(2-aminoethoxy)-5 -Fluoro-1,2-benzisoxazole, compound 1-22: 3-(2-aminoethoxy)-5-fluoro-4-methyl-1,2-benzisoxazole, compound 1 -31: 3-(2-aminoethylthio)-5-fluoro-1,2-benzisoxazole, compound 1-53: 3-(2-aminoethoxy)-5-chloro-1, 2-Benzisoxazole, compound 1-59: 3-(2-aminoethoxy)-5,7-dichloro-1,2-benzisoxazole, compound 1-62: 3-(2 -aminoethylthio)-5-chloro-7-methyl-1,2-benzisoxazole, compound 1-69: 3-(2-aminoethylthio)-5-chloro-1,2- Benzisoxazole, compound 1-85: 3-(2-aminoethoxy)-6-chloro-1,2-benzisoxazole, compound 1-97: 3-(2-aminoethoxy )-7-chloro-1,2-benzisoxazole, compound 1-119: 3-(2-aminoethoxy)-5-bromo-1,2-benzisoxazole, compound 1-142 : 3-(2-aminoethoxy)-5-methyl-1,2-benzisoxazole, compound 1-151: 3-(2-aminoethylthio)-5-methyl-1, 2-Benzisoxazole, compound 1-160: 3-(2-aminoethoxy)-6-methyl-1,2-benzisoxazole, compound 1-169: 3-(2-amino Ethoxy)-7-methyl-1,2-benzisoxazole, compound 1-193: 3-(2-aminoethoxy)-5-methoxy-1,2-benzisoxazole Azole, compound 1-197: 3-(2-aminoethylthio)-5-methoxy-1,2-benzisoxazole, compound 1-224: 3-(2-aminoethoxy)- 5-Difluoromethoxy-1,2-benzisoxazole, compound 1-269: 3-(2-aminoethoxy)-5-fluoro-4-methylthio-1,2-benzo Isoxazole, compound 1-422: 3-(2-aminoethoxy)-5-methoxycarbonyl-1,2-benzisoxazole, compound 1-521: 3-(2-aminoethoxy )-5-nitro-1,2-benzisoxazole, compound 1-537: 3-(2-aminoethylthio)-5-nitro-1,2-benzisoxazole, compound 1 -572: 3-(2-aminoethoxy)-4-cyano-1,2-benzisoxazole, or compound 3-2: 3-(2-aminoethoxy)pyrido[3, 2-d] isoxazole.

〔方法B〕〔方法C〕

〔方法D〕

〔方法E〕

〔方法F〕

〔方法G〕

The synthesis method of the compound of the present invention is shown below. [Method A]

[Method B] [Method C]

[method D]

[Method E]

[Method F]

[Method G]

In the above formula, R ¹ , R ² , m, n, ring A and X are as above, when R ¹ _a represents C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkane Oxycarbonyl, carboxyl, dithiocarboxy or (C ₁ -C ₆ alkylthio) thiocarbonyl group, R ¹ _b represents C ₁ -C ₆ alkyl, R ³ represents an ester residue, R ³ _a represents C ₁ -C ₄ alkyl, R ⁴ represents a protected amino group, Y represents a hydroxyl group or a leaving group, Z represents a halogen atom and m' represents an integer of 1 or 2.

The C ₁ -C ₆ alkyl in R ¹ _a or the C ₁ -C ₆ alkyl moiety in the C ₁ -C ₆ alkylthio group is as described above; R ¹ _a can be, for example, methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4 -Methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1 -Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, methylthio, ethylthio propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio Base, 1-ethylpropylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3,3- Dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio , 2,3-dimethylbutylthio, 2-ethylbutylthio, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl , tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, carboxyl, dithiocarboxy or (methylthio)thiocarbonyl groups, preferably C ₁ -C ₄ alkyl, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkoxycarbonyl, carboxyl or dithiocarboxy groups, and more preferably methyl, ethyl, methylthio, ethylthio or carboxyl.

The C ₁ -C ₆ alkyl in R ¹ _h is as described above and can be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl , isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methyl Pentyl, 3,3-dimethylpentyl, 2,2-dimethylpentyl, 1,1-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl A pentyl, 2,3-dimethylpentyl or 2-ethylbutyl group, preferably a C ₁ -C ₄ alkyl group, and more preferably a methyl or ethyl group.

The ester residue in R ³ can be, for example, a C ₁ -C ₆ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl; or a substituted C ₁ -C ₄ alkyl group (the substituent may be a halogen atom, C ₁ -C ₄ alkoxy, halogen- or C ₁ -C ₄ alkoxy-substituted C ₁ -C ₄ alkoxy group, C ₆ -C ₁₄ aryl group or 1-3 selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, halogen and cyano C ₆ -C ₁₄ aryl substituted by groups) such as 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-dibromoethyl, 2,2,2-trichloroethyl Base, 3-fluoropropyl, 4-chlorobutyl, methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, n-propoxymethyl, iso Propoxymethyl, n-butoxymethyl, tert-butoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl base, 3-methoxypropyl-4-methoxybutyl, fluoromethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl , 3-fluoropropoxymethyl, 4-chlorobutoxyethyl, dibromomethoxyethyl, 2-chloroethoxypropyl, fluoromethoxybutoxy, 2-methoxyethyl Oxymethyl, Ethoxymethoxyethyl, Methoxyethoxypropyl, Methoxyethoxybutyl, Benzyl, Phenylethyl, 3-Phenylpropyl, 4-Phenyl Butyl, α-naphthylmethyl, β-naphthylmethyl, benzhydryl, trityl, α-naphthyldiphenylmethyl, 9-anthracenylmethyl, 4-methylbenzyl , 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitro Benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis(2-nitrophenyl) Methyl or piperonyl groups, preferably C ₁ -C ₄ alkyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trichloroethyl, methoxymethyl Base, ethoxymethyl, fluoromethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, benzyl, phenethyl, 4- methylbenzyl, 2,4,6-trimethylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 4-chlorobenzyl or 4-cyanobenzyl groups, and more preferably Methyl, ethyl, 2,2,2-trichloroethyl, methoxymethyl, ethoxymethyl, fluoromethoxymethyl, 2,2,2-trichloroethoxymethyl, Benzyl, phenethyl, 4-methylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 4-chlorobenzyl or 4-cyanobenzyl groups. Particularly preferred are methyl or ethyl.

The C ₁ -C ₄ alkyl group in R ³ _a can be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl , and more preferably methyl.

The protecting group of the protected amino group in ^R is not specifically limited and can be any group commonly used for the protection of amino groups, such as C ₁ -C ₆ alkanoyl such as formyl, acetyl , propionyl, butyryl, isobutyryl, valeryl, pivaloyl, valeryl, isovaleryl or hexanoyl groups; halogen- or C ₁ -C ₄ alkoxy-substituted C ₁ -C ₄ chains Alkanoyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, 3-fluoropropionyl, 4,4-dichlorobutyryl, methoxyacetyl, butylacetyl, ethoxy ylpropionyl or propoxybutyryl groups; unsaturated C ₁ -C ₄ alkanoyl groups such as acryloyl, propioloyl, methacrvloyl, crotonyl or methacryloyl (isocrotonoyl) groups; _C 6 -C ₁₀ arylcarbonyl substituted by halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxycarbonyl, C ₆ -C ₁₀ aryl or nitro Groups such as benzoyl, α-naphthoyl, β-naphthoyl, 2-fluorobenzoyl, 2-bromobenzoyl, 2,4-dichlorobenzoyl, 6-chloro-α-naphthoyl Acyl, 4-toluoyl, 4-propylbenzoyl, 4-tert-butylbenzoyl, 2,4,6-trimethylbenzoyl, 6-ethyl-α-naphthoyl, 4 -Methoxybenzoyl, 4-propoxybenzoyl, 4-tert-butoxybenzoyl, 6-ethoxy-α-naphthoyl, 2-ethoxycarbonylbenzoyl, 4-tert Butoxycarbonylbenzoyl, 6-methoxycarbonyl-α-naphthoyl, 4-phenylbenzoyl, 4-phenyl-α-naphthoyl, 6-α-naphthylbenzoyl, 4- Nitrobenzoyl, 2-nitrobenzoyl or 6-nitro-α-naphthoyl group; C ₁ -C ₄ alkane which may be substituted by halogen or tri-C ₁ -C ₄ alkylsilyl Oxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, chloromethoxycarbonyl, 2,2, 2-Trichloroethoxycarbonyl, 2-fluoropropoxycarbonyl, 2-bromo-tert-butoxycarbonyl, 2,2-dibromo-tert-butoxycarbonyl, triethylsilylmethoxycarbonyl, 2-trimethyl C ₂ -C ₅ alkenyloxycarbonyl groups such as ethyleneoxycarbonyl , allyloxycarbonyl, 1,3-butadieneoxycarbonyl or 2-penteneoxycarbonyl groups; aryldicarbonyl groups such as phthaloyl; aralkyl groups such as benzyl, phenethyl , 3-phenylpropyl, 4-phenylbutyl, α-naphthylmethyl, β-naphthylmethyl, benzhydryl, trityl, α-naphthyldiphenylmethyl or 9 - anthracenylmethyl group; or a C ₇ -C ₁₅ arylalkoxycarbonyl group which may be substituted by methoxy or nitro such as benzyloxycarbonyl, (1-phenyl)benzyloxycarbonyl, α-naphthyl Methoxycarbonyl, β-naphthylmethoxycarbonyl, 9-anthracenylmethoxycarbonyl, p-methoxybenzyloxycarbonyl or p-nitrobenzyloxycarbonyl, preferably C ₁ -C ₄ alkanoyl, tri Fluoroacetyl, methoxyacetyl, benzoyl, α-naphthoyl, β-naphthoyl, methoxybenzoyl, nitrobenzoyl, C ₁ -C ₄ alkoxycarbonyl, methoxycarbonyl , ethoxycarbonyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, triethylsilylmethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, ethyleneoxycarbonyl, allyl Oxycarbonyl, phthaloyl, benzyl, benzyloxycarbonyl or nitrobenzyloxycarbonyl groups, and more preferably formyl, acetyl, benzoyl, 4-methoxybenzoyl, 4-nitrophenyl Formyl, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, phthaloyl, benzyl, benzyloxycarbonyl or p-nitrobenzyloxycarbonyl groups. Particularly preferred is tert-butoxycarbonyl.

The leaving group in Y is not particularly limited, as long as it can usually be removed as a nucleophilic residue and can be, for example, a halogen atom such as fluorine, chlorine, bromine or iodine atom; C ₁ -C ₄ alkanesulfonyl Oxy groups such as methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy or butanesulfonyloxy groups; halogenated C ₁ -C ₄ alkylsulfonyloxy groups such as trifluoromethanesulfonyl Acyloxy, 2,2,2-trichloroethanesulfonyloxy, 3,3,3-tribromopropanesulfonyloxy or 4,4,4-trifluorobutanesulfonyloxy groups; or C ₆ -C ₁₀ arylsulfonyloxy groups containing 1-3 C ₁ -C ₄ alkyl groups such as benzenesulfonyloxy, α-naphthalenesulfonyloxy, β-naphthalenesulfonyloxy, p-toluene A sulfonyloxy, 4-tert-butylbenzenesulfonyloxy, 2,4,6-tritosyloxy or 6-ethyl-α-naphthalenesulfonyloxy group. Chlorine, bromine, iodine atoms are preferred; methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, 2,2,2-trichloroethanesulfonyloxy; benzenesulfonyloxy, toluenesulfonyl Acyloxy or 2,4,6-tritosyloxy groups, and more preferably chlorine, bromine, iodine atoms; methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p- Toluenesulfonyloxy or 2,4,6-trimethylbenzenesulfonyloxy.

The halogen atom in Z may be, for example, a fluorine, chlorine, bromine or iodine atom, and is preferably a fluorine or chlorine atom.

The raw material compound (XIII) or (XIX) of the present invention is a known compound or can be synthesized by known methods [for example Chem.Abstr., 49,11594(1955)., Tetrahedron, 38,1457(1982)., Japanese Patent Kokai Hei 3-294267, Synth. Commun., 9, 731 (1979)., J. Org. Chem., 44, 3292 (1979) or Chem. Ber., 100, 954 (1967)].

The compound of general formula (XVII) can be a known compound or can be synthesized according to a known method [eg Synthesis, 366 (1990)., or J. Med. Chem., 34, 1258 (1991).].

The compound of general formula (XV) wherein ring A is a pyridyl ring can be a known compound or can be synthesized by known methods [for example J.Med.Chem., 32,2116 (1989) or J.Chem.Soc.(C ), 172(1968)].

Method A is a synthesis method of the compound (I).

In Step A1, the compound of general formula (XIII) is treated with hydroxylamine in an inert solvent in the presence of a base to prepare the compound of general formula (XIV).

The solvent used is not particularly limited as long as it does not interfere with the reaction and can dissolve a certain amount of the raw material, which may be, for example, aliphatic hydrocarbons such as hexane, heptane, petrolatum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or Xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl oxyethane or diglyme; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol; amides such as formamide, dimethylformamide, dimethylacetamide or hexa methylphosphoramide; sulfoxides such as dimethylsulfoxide or sulfolane; water or aqueous mixtures of the aforementioned organic solvents. Ethers, alcohols, amides, sulfoxides or aqueous mixtures of these organic solvents are preferred, and alcohols (in particular methanol or ethanol) or aqueous alcohols (in particular aqueous methanol or aqueous ethanol) are more preferred.

The base used may be, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; an alkali metal hydride such as sodium hydride, potassium hydride or Lithium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or lithium methoxide; alkali metal thiolates such as methyl sulfide Sodium alkoxide or sodium ethanethiolate; Organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2, 2,2]octane (DABCO) or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU); alkyllithium such as methyllithium, ethyllithium or butyllithium ; lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide. Preference is given to alkali metal carbonates, alkali metal hydroxides or alkali metal alkoxides, and more preferably alkali metal hydroxides (in particular sodium hydroxide or potassium hydroxide).

The reaction temperature may vary depending on the raw materials and reagents, but is usually in the range of -10 to 100°C and preferably in the range of 0 to 50°C.

The reaction time may vary depending on the raw materials, reagents or reaction temperature, but is usually in the range of 10 minutes to 10 hours and preferably in the range of 30 minutes to 5 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, after the reaction is completed, the solvent is removed by evaporation, water is added to the residue to acidify the aqueous layer, and the precipitated compound is filtered. Alternatively, water is added to the reaction mixture and a hydrophobic solvent (such as benzene, diethyl ether, ethyl acetate) is added to extract the target compound. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated to obtain the target compound. The resulting object compound can be purified by a conventional method such as recrystallization, reprecipitation, chromatography or converted into a salt by adding an acid, if necessary.

In step A2, the compound of general formula (XV) can be prepared from general formula (XIV) according to the reaction described in Chem. Ber., 100, 954 (1967) by the following method. (1) Reaction with thionyl chloride, phosgene or their equivalents (such as diphosgene) in an inert solvent, followed by (2) reaction with a base in an inert solvent.

The solvents used in steps (1) and (2) are not particularly limited as long as they do not interfere with the reaction and can dissolve a certain amount of the raw materials. They can be, for example, aliphatic hydrocarbons such as hexane, heptane, petrolatum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorine Benzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or diglyme; or sulfoxides such as dimethyl sulfoxide or tetrahydrothiophene sulfone. Preference is given to halogenated hydrocarbons (in particular dichloromethane, chloroform, carbon tetrachloride or dichloroethane) or ethers (in particular diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane), and more preferably ethers (especially diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane).

The base used in step (2) can be, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; an alkali metal hydride such as hydrogen Lithium, sodium hydride, or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or lithium methoxide; alkali metal sulfur Alkoxides such as sodium methyl mercaptide or sodium ethanethiolate; organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-di Methylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazepine Heterobicyclo[2,2,2]octane (DABCO) or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU); alkyllithium such as methyllithium or butyl lithium; or lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide. Organic amines are preferred, and more preferred are triethylamine, tributylamine, diisopropylethylamine, pyridine, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4 - Diazabicyclo[2,2,2]octane (DABCO) or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU). Particularly preferred is triethylamine.

The reaction temperature of the steps (1) and (2) may vary depending on the raw materials or reagents, but is usually in the range of -10 to 100°C and preferably in the range of 0 to 50°C.

The reaction time of the steps (1) and (2) may vary depending on the raw materials, reagents or reaction temperature, but generally ranges from 10 minutes to 10 hours and preferably ranges from 15 minutes to 5 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, by distilling off the solvent, adding water to the reaction mixture to acidify the aqueous layer, and filtering the precipitated product; or by adding a hydrophobic solvent (such as benzene, ether, ethyl acetate), washing the extract with water, and removing it After drying over anhydrous magnesium sulfate and distilling off the solvent, the target compound was isolated. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

In step A3, the compound (XV) is reacted with a halogenating agent in the presence or absence of a base (preferably in the presence of a base) in an inert solvent or without a solvent to synthesize the compound (XVI).

The halogenating agent may be, for example, phosphorus oxychloride, phosphorus oxybromide, phosphorus oxyiodide or phosphorus pentachloride, and is preferably phosphorus oxychloride, phosphorus pentachloride or a mixture thereof.

The solvents used are not particularly limited as long as they do not interfere with the reaction and can dissolve a certain amount of the raw materials, and they may be, for example, aliphatic hydrocarbons such as hexane, heptane, petrolatum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene ; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethane or diglyme; or sulfoxides such as dimethylsulfoxide or sulfolane, preferably halogenated hydrocarbons (especially dichloromethane) or ethers (especially tetrahydrofuran or dioxane), and More preferred are ethers (in particular diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane).

The base used may be, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; an alkali metal hydride such as lithium hydride, sodium hydride or Potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or lithium hydroxide; or organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine , 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4,3,0]nonan-5 -ene, 1,4-diazabicyclo[2,2,2]octane (DABCO) or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), preferably Alkali metal carbonates or organic amines, and more preferably organic amines (especially triethylamine or pyridine).

The reaction temperature may vary depending on the raw materials or reagents, but is usually in the range of 0 to 150°C and preferably in the range of 10 to 100°C.

The reaction time may vary depending on the raw materials, reagents or reaction temperature, but is usually in the range of 30 minutes to 10 hours and preferably in the range of 1 to 5 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, by distilling off the solvent, water is added to the reaction mixture, followed by addition of a hydrophobic solvent (such as benzene, diethyl ether, ethyl acetate) to extract the compound, the organic layer is washed with water, dried over anhydrous magnesium sulfate and evaporated. The compound of interest is isolated by removal of the solvent. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

In step 4, the compound (XVI) is reacted with the compound of the general formula (XVII) in an inert solvent in the presence of a base to synthesize the compound (XVIII).

The solvents used are not particularly limited as long as they do not interfere with the reaction and can dissolve a certain amount of the raw materials, and they may be, for example, aliphatic hydrocarbons such as hexane, heptane, petrolatum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene ; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy ethane or diglyme; or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; or sulfoxides such as dimethylsulfoxide or sulfolane. Ethers, amides or sulfoxides are preferred, and ethers (especially diethyl ether, tetrahydrofuran or dioxane) or amides (especially dimethylformamide) are more preferred.

The base used may be, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; an alkali metal hydride such as lithium hydride, sodium hydride or Potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or lithium hydroxide; or organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine , 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4,3,0]nonan-5 -ene, 1,4-diazabicyclo[2,2,2]octane (DABCO) or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU); alkane Lithium radicals such as methyllithium, ethyllithium or butyllithium; lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide, preferably alkali metal carbonates, alkali metal hydrides or organic amines , and more preferably an alkali metal carbonate (especially sodium carbonate or potassium carbonate) or an alkali metal hydride (especially sodium hydride).

To accelerate the reaction, a crown ether such as dibenzo-18-crown-6 may be added.

The reaction temperature may vary depending on the raw materials or reagents, but is usually in the range of -10 to 150°C and preferably in the range of 0 to 80°C.

The reaction time may vary depending on the raw materials, reagents or reaction temperature, but is usually in the range of 30 minutes to 30 hours and preferably in the range of 1 to 10 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, by neutralizing the reaction mixture appropriately, filtering off insolubles, if present, removing the solvent by evaporation, adding water to the reaction mixture followed by adding a hydrophobic solvent (e.g. benzene, diethyl ether, ethyl acetate) to extract For the compound, the organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off to isolate the target compound. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

In step A5, the amino protecting group is removed to obtain the compound (I).

Removal of the amino protecting group can vary depending on the type of the protecting group, and can be carried out by methods known in general organic synthetic chemistry as described below.

When the amino protecting group is a C ₁ -C ₆ alkanoyl group (preferably formyl or acetyl); a C ₆ -C ₁₀ arylcarbonyl group (preferably benzoyl); can be replaced by halogen or three C ₁ - C ₄ alkylsilyl substituted C ₁ -C ₄ alkoxycarbonyl group (preferably methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-bromo - tert-butoxycarbonyl or 2,2-dibromo-tert-butoxycarbonyl); C ₂ -C ₅ alkenyloxycarbonyl groups which may be substituted by methoxy or nitro (preferably ethyleneoxycarbonyl) or which may be substituted by methyl Oxy- or nitro-substituted C ₇ -C ₁₅ arylalkoxycarbonyl groups (preferably benzyloxycarbonyl, (1-phenyl)benzyloxycarbonyl, 9-anthracenylmethoxycarbonyl, p-methoxybenzyloxy carbonyl or p-nitrobenzyloxycarbonyl), it can be removed by treatment with an acid in an inert or aqueous solvent. In this case, the target product can be obtained in the form of a salt.

The acid used may be, for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or trifluoroacetic acid and is preferably any one of hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid.

The solvents used are not particularly limited as long as they do not interfere with the reaction and can dissolve a certain amount of the raw materials, and they may be, for example, aliphatic hydrocarbons such as hexane, heptane, petrolatum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene ; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethane or diglyme; or esters such as methyl acetate or ethyl acetate; alcohols such as methanol, ethanol, propanol, isopropanol or butanol; amides such as formamide, dimethylformamide, dimethylformamide, dimethylformamide, acetamide or hexamethylphosphoramide; sulfoxides such as dimethyl sulfoxide or sulfolane; fatty acids such as formic acid or acetic acid; or water or aqueous mixtures of the above solvents, preferably halogenated hydrocarbons, ethers, alcohols, fatty acids; water or aqueous mixtures of the aforementioned solvents, and more preferably halogenated hydrocarbons (especially dichloromethane), ethers (especially tetrahydrofuran or dioxane), fatty acids (especially acetic acid), water or aqueous mixtures of the aforementioned solvents.

The reaction temperature may vary depending on the raw material, solvent or acid used, but is usually in the range of -10 to 150°C and preferably in the range of 0 to 60°C.

The reaction time may vary depending on the raw material, solvent or acid used, but is usually in the range of 5 minutes to 20 hours and preferably in the range of 10 minutes to 5 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, by filtering the target product precipitated out of the reaction mixture, or by appropriately neutralizing the reaction mixture, removing the solvent by evaporation, adding water to the reaction mixture, followed by adding a hydrophobic solvent (such as benzene, diethyl ether, etc. , ethyl acetate) to extract the compound, the organic layer was washed with water, dried with anhydrous magnesium sulfate and the solvent was evaporated to isolate the target compound. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

When the amino protecting group is an alkanoyl group, an arylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an aryldicarbonyl group, an aralkyl group or an aryl alkoxycarbonyl group, it can be The solvent is removed by alkali treatment.

The base used may be, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; an alkali metal hydride such as lithium hydride, sodium hydride or Potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or lithium methoxide; alkali metal thiolates such as methyl sulfide Sodium alkoxide or sodium ethanethiolate, more preferably alkali metal carbonate (especially sodium carbonate or potassium carbonate), alkali metal hydroxide (especially sodium hydroxide or potassium hydroxide), alkali metal alkoxide (especially is sodium methoxide, sodium ethoxide or potassium tert-butoxide) or an organic amine (especially hydrazine or methylamine).

The solvents used are not particularly limited as long as they do not interfere with the reaction and can dissolve a certain amount of the raw materials, and they may be, for example, aliphatic hydrocarbons such as hexane, heptane, petrolatum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene ; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethane or diglyme; alcohols such as methanol, ethanol, propanol, isopropanol or butanol; amides such as dimethylacetamide or hexamethylphosphoramide; sulfoxides such as dimethylsulfoxide or tetrahydro Thiophene sulfone; or an aqueous mixture of the above solvents, preferably halogenated hydrocarbons, ethers, alcohols or aqueous mixtures of the above solvents, and more preferably ethers (especially tetrahydrofuran or dioxane), alcohols (especially methanol or ethanol) or the above solvents aqueous mixture.

The reaction temperature may vary depending on the raw material, solvent or base used, but is usually in the range of -10 to 150°C and preferably in the range of 0 to 50°C.

The reaction time may vary depending on the raw material, solvent or base used, but is usually in the range of 30 minutes to 20 hours and preferably in the range of 1 to 5 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, by filtering the precipitated product from the reaction mixture, or removing the solvent by evaporation, adding water to make the aqueous layer basic to filter off the precipitated product, or adding a hydrophobic solvent (such as benzene, diethyl ether, ethyl acetate) , to extract the compound, the organic layer containing the target product was washed with water, dried with anhydrous magnesium sulfate and the solvent was evaporated to obtain the target compound. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

When the amino protecting group is a tert-butoxycarbonyl group, it can also be removed by treatment with a silyl compound or a Lewis acid in an inert solvent.

The silyl compound used may be, for example, trimethylsilyl chloride, trimethylsilyl iodide or trimethylsilyl triflate, and the Lewis acid used may be aluminum chloride.

The solvents used are not particularly limited as long as they do not interfere with the reaction and can dissolve a certain amount of the raw materials, and they may be, for example, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride; ethers such as diethyl ether, tetrahydrofuran or dioxane or a nitrile such as acetonitrile, preferably a halogenated hydrocarbon (especially dichloromethane or chloroform) or a nitrile (especially acetonitrile).

The reaction temperature may vary depending on the raw materials, reagents or solvents, but is usually in the range of -20 to 100°C and preferably in the range of 0 to 50°C.

The reaction time may vary depending on the raw materials, reagents, solvents or the reaction temperature, but is usually in the range of 10 minutes to 10 hours and preferably in the range of 30 minutes to 3 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, the solvent is removed by evaporation, water is added to the reaction mixture to make the aqueous layer basic and the precipitated product is filtered off, or a hydrophobic solvent (such as benzene, ether, ethyl acetate) is added to extract the compound, containing the desired product The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off to isolate the target compound. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

In the case where the amino protecting group is an allyloxycarbonyl group, it can be used to remove the aralkyl group by catalytic hydrogenation of palladium and triphenylphosphine or nickel tetracarbonyl. The similar reaction conditions include solvent, reaction temperature and time, etc. condition removed.

In case the amino-protecting group is an aralkyl or C ₇ -C ₁₁ arylalkoxycarbonyl group, it can be treated with a reducing agent in an inert solvent (preferably catalytic hydrogenation in the presence of a catalyst) or with Oxidizing agents are easily removed.

The solvents used in the catalytic hydrogenation to remove the protective group are not particularly limited as long as they do not participate in the reaction and may be, for example, aliphatic hydrocarbons such as hexane or cyclohexane; aromatic hydrocarbons such as toluene, benzene or xylene ; ethers such as diethyl ether, tetrahydrofuran or dioxane; esters such as ethyl acetate or propyl acetate; alcohols such as methanol, ethanol or isopropanol; fatty acids such as formic acid and acetic acid; Aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, alcohols, fatty acids or aqueous mixtures of these solvents are preferred, and alcohols (in particular methanol or ethanol), fatty acids (in particular formic acid or acetic acid) or aqueous mixtures of these solvents are more preferred.

The catalyst used is not particularly limited as long as it is generally used in catalytic hydrogenation and may be, for example, palladium-carbon, Raney nickel, rhodium-alumina or palladium-barium sulfate. Preference is given to palladium-carbon or Raney nickel.

The pressure of the hydrogen gas is not particularly limited, but is generally in the range of 1 to 10 atmospheres and preferably 1 atmosphere.

The reaction temperature may vary depending on the raw material, solvent or catalyst used, but is usually in the range of 0 to 100°C and preferably in the range of 10 to 50°C.

The reaction time may vary depending on the raw material, solvent, catalyst used or the reaction temperature, but is usually in the range of 15 minutes to 10 hours and preferably in the range of 30 minutes to 3 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, by filtering off the catalyst and then evaporating the solvent, adding water to make the aqueous layer alkaline and filtering off the precipitated product, or by adding a hydrophobic solvent (such as benzene, ether, ethyl acetate) to extract the compound, containing The organic layer of the target product was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated to isolate the target compound. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

The solvents used in the oxidation reaction for removing the protecting group are not particularly limited as long as they do not participate in the reaction and may be, for example, ketones such as acetone; halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride; nitriles such as acetonitrile; ethers such as diethyl ether, tetrahydrofuran or dioxane; amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide; sulfoxides such as dimethylsulfoxide; or aqueous mixtures of these organic solvents. Preferably any one of ketones, halogenated hydrocarbons, nitriles, ethers, amides, sulfoxides or aqueous mixtures of these solvents, and more preferably ketones (especially acetone), halogenated hydrocarbons (especially dichloromethane), nitriles (especially acetonitrile), amides (especially hexamethylphosphoramide), sulfoxides (especially dimethylsulfoxide) or aqueous mixtures of these solvents.

The oxidizing agent used can be, for example, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), and preferably ammonium cerium nitrate (CAN) or 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ).

The reaction temperature may vary depending on the raw material, solvent or oxidizing agent used, but is usually in the range of 0 to 150°C and preferably in the range of 10 to 50°C.

The reaction time may vary depending on the compound, the solvent or the oxidizing agent used, but generally ranges from 15 minutes to 24 hours and preferably ranges from 30 minutes to 5 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, by filtering off the oxidizing agent and then evaporating the solvent, adding water to make the aqueous layer basic and filtering off the precipitated product, or by adding a hydrophobic solvent (such as benzene, ether, ethyl acetate), to extract the compound, containing the The organic layer of the target product was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated to isolate the target compound. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

Method B is a method for synthesizing said compound (XVIIIa) wherein X is oxygen among intermediate compounds (XVIII) in method A.

In step B1, the compound (XVIIIa) is prepared by reacting the compound (XV) with a compound of the general formula (XVIIa).

When Y is a hydroxyl group, the reaction is carried out according to the Mitsunobu reaction described in Bull. The compound (XV) is dehydrocondensed with the corresponding compound (XVIIa).

The solvents used are not particularly limited as long as they do not interfere with the reaction and can dissolve a certain amount of the raw materials, and they may be, for example, aliphatic hydrocarbons such as hexane, heptane, petrolatum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene ; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy ethane or diglyme. Aliphatic hydrocarbons, aromatic hydrocarbons or ethers are preferred, and ethers (especially diethyl ether or tetrahydrofuran) are more preferred.

The phosphine-compound used can be, for example, tri-C ₁ -C ₆ -alkylphosphine such as trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine or trihexylphosphine; triC ₆ - C ₁₀ arylphosphine such as triphenylphosphine, triindenylphosphine or trinaphthylphosphine; or tri-C ₆ -C ₁₀ arylphosphine with C ₁ -C ₄ alkyl substituents such as tolyldiphenylphosphine, Tricresylphosphine, triscortylphosphine, tributylphenylphosphine or tris-6-ethyl-2-naphthylphosphine. Preference is given to tri-C ₁ -C ₆ alkylphosphine (in particular trimethylphosphine, triethylphosphine, tripropylphosphine or tributylphosphine) or tri-C ₆ -C ₁₀ arylphosphine (in particular triphenylphosphine , triindenylphosphine or trinaphthylphosphine), and more preferably triC ₆ -C ₁₀ arylphosphine (especially triphenylphosphine).

The azo-compounds used can be, for example, di- _C1 - _C4- alkyl azodicarboxylates such as dimethyl azodicarboxylate, diethyl azodicarboxylate, dipropyl azodicarboxylate or azodicarboxylate dibutyl and preferably dimethyl azodicarboxylate or diethyl azodicarboxylate.

The reaction temperature may vary depending on the raw materials or reagents, but is usually in the range of -10 to 100°C and preferably in the range of 0 to 50°C.

The reaction time may vary depending on the raw materials, reagents or reaction temperature, but is usually in the range of 15 minutes to 48 hours and preferably in the range of 30 minutes to 24 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, by filtering off possible insolubles and removing the solvent by evaporation, or by adding water to the residue after removal of the solvent, adding a hydrophobic solvent (such as benzene, diethyl ether, ethyl acetate) to extract the compound, washing with water , dried over anhydrous magnesium sulfate and distilled off the solvent to obtain the target compound. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

When Y is a leaving group, the compound (XVIIIa) is prepared by reacting the compound (XV) with the corresponding compound (XVIIa) in the presence of a base in an inert solvent.

The solvent used is not particularly limited so long as it does not interfere with the reaction and can dissolve a certain amount of the starting material. They can be, for example, aliphatic hydrocarbons such as hexane, heptane, petrolatum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorine benzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diglyme; amides such as formamide, dimethylformamide, di methylacetamide or hexamethylphosphoramide; or sulfoxides such as dimethylsulfoxide or sulfolane. Amides or sulfoxides are preferred, and amides (in particular dimethylformamide, dimethylacetamide or hexamethylphosphoramide) are more preferred.

The base used may be, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; an alkali metal hydride such as lithium hydride, sodium hydride or Potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or lithium methoxide; alkali metal thiolates such as methyl sulfide Sodium alkoxide or sodium ethanethiolate; Organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2, 2,2]octane (DABCO) or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU); alkyllithium such as methyllithium, ethyllithium or butyllithium ; lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide. Alkali metal carbonates, alkali metal hydrides or alkali metal hydroxides are preferred, and alkali metal hydrides (especially sodium hydride) are more preferred.

To accelerate the reaction, a crown ether such as dibenzo-18-crown-6 may be added.

The reaction temperature may vary depending on the raw materials and reagents, but is usually in the range of -10 to 100°C and preferably in the range of 0 to 50°C.

The reaction time may vary depending on the raw materials, reagents or reaction temperature, but is usually in the range of 30 minutes to 20 hours and preferably in the range of 1 to 5 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example neutralize the reaction mixture appropriately, filter off insolubles if present, remove the solvent by evaporation, add water to the residue, add a hydrophobic solvent (e.g. benzene, diethyl ether, ethyl acetate) to extract the compound , the organic layer containing the target compound was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated to isolate the target compound. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

Method C is another method for synthesizing the compound (XV), which is an intermediate in method A or a starting material in method B.

In step C1, a compound of general formula (XX) is prepared by reacting a compound of general formula (XIX) with a diazo C ₁ -C ₄ alkane.

The diazo C ₁ -C ₄ alkane can be any one of diazomethane, diazoethane, diazopropane or diazobutane and is preferably diazomethane.

The solvent used is not particularly limited so long as it does not interfere with the reaction and can dissolve a certain amount of the raw material. They can be, for example, aliphatic hydrocarbons such as hexane, heptane, petrolatum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorine benzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diglyme; esters such as methyl acetate or ethyl acetate; or the above mixture of solvents. Preference is given to halogenated hydrocarbons, ethers, esters or mixtures of the aforementioned solvents, and more preference is given to ethers (especially diethyl ether), esters (especially ethyl acetate) or mixtures of the aforementioned solvents.

The reaction temperature may vary depending on the raw materials and reagents, but is usually in the range of -10 to 100°C and preferably in the range of 10 to 50°C.

The reaction time may vary depending on the raw materials, reagents or reaction temperature, but is usually in the range of 10 minutes to 10 hours and preferably in the range of 15 minutes to 3 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. The target compound is isolated, for example, by evaporative removal of the solvent. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

In step C2, the compound of general formula (XXI) is prepared by reacting the compound (XX) with hydroxylamine in the presence of a base in an inert solvent.

The solvent and base are as described in step A1.

The reaction temperature may vary depending on the raw materials and reagents, but is usually in the range of -10 to 100°C and preferably in the range of 10 to 50°C.

The reaction time may vary depending on the raw materials, reagents or reaction temperature, but is usually in the range of 10 minutes to 10 hours and preferably in the range of 30 minutes to 5 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example by removing the solvent by evaporation, adding water to the residue to make the aqueous layer acidic and filtering the precipitated product, or by adding water to the reaction mixture, making the aqueous layer acidic, adding a hydrophobic solvent (e.g. benzene, diethyl ether, ethyl acetate) to extract the target compound, the extracted organic layer was washed with water, dried with anhydrous magnesium sulfate and the solvent was evaporated to isolate the target compound. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

In step C3, the compound (XV) is prepared by reacting the compound (XXI) with a base in an inert solvent.

The solvent used is not particularly limited so long as it does not interfere with the reaction and can dissolve a certain amount of the starting material. They can be, for example, aliphatic hydrocarbons such as hexane, heptane, petrolatum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorine substituted benzene or dichlorobenzene; or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diglyme; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; sulfoxides such as dimethylsulfoxide or sulfolane; or water. Amides, sulfoxides or water are preferred, and water is more preferred.

The base used may be, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; an alkali metal hydride such as lithium hydride, sodium hydride or Potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4,3,0]nonan-5- ene, 1,4-diazabicyclo[2,2,2]octane (DABCO) or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU); alkyl Lithium such as methyllithium, ethyllithium or butyllithium; or lithium alkylamide such as lithium diisopropylamide or lithium dicyclohexylamide. Alkali metal carbonates, alkali metal bicarbonates or alkali metal hydroxides are preferred, and alkali metal hydroxides (especially sodium hydroxide or potassium hydroxide) are more preferred.

The reaction temperature may vary depending on the raw materials and reagents, but is usually in the range of 0 to 150°C and preferably in the range of 10 to 100°C.

The reaction time may vary depending on the raw materials, reagents or reaction temperature, but is usually in the range of 10 minutes to 10 hours and preferably in the range of 15 minutes to 5 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, by making the reaction mixture acidic and filtering the precipitated product or making the reaction mixture acidic, adding a hydrophobic solvent (such as benzene, diethyl ether, ethyl acetate) to extract the compound, the compound containing the target compound The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated to isolate the target compound. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

Method D is a synthesis method of said compound (XXIII) in which the substituent on ring A of intermediate compound (XVIII) in method A contains R ¹ _a .

In step D1, by reacting the compound (XXII) with a halogenated C ₁ -C ₆ alkane, carbon dioxide, carbon disulfide, diC ₁ -C ₆ alkyl disulfide, dicarbonate in an inert solvent in the presence of a base, C ₁ -C ₆ Alkyl esters, S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate or S-(trifluoromethyl)-3,7-dinitrodibenzothiophene The compound (XXIII) is prepared by reacting triflate (preferably halogenated C ₁ -C ₆ alkane or carbon dioxide).

The halogenated C ₁ -C ₆ alkane can be, for example, methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl iodide, propane bromide, butane iodide, pentane iodide or hexyl iodide. Methyl bromide or methyl iodide is preferred, and methyl iodide is more preferred.

The diC ₁ -C ₆ alkyl disulfide can be, for example, dimethyl disulfide, diethyl disulfide, dipropyl disulfide, dibutyl disulfide, diamyl disulfide or diamyl disulfide Hexyl disulfide, and preferably dimethyl disulfide or diethyl disulfide.

Di-C ₁ -C ₆ alkyl carbonates can be, for example, dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, di-sec-butyl carbonate, di-tertiary carbonate butyl, dipentyl carbonate or dihexyl carbonate, and preferably dimethyl carbonate or diethyl carbonate.

The solvent used is not particularly limited so long as it does not interfere with the reaction and can dissolve a certain amount of the raw material. They can be, for example, aliphatic hydrocarbons such as hexane, heptane, petrolatum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorine Benzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diglyme; diamines such as N, N, N', N' - Tetramethylenediamine; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide or hexamethylphosphoramide; or sulfoxides such as dimethylsulfoxide or sulfolane . Ethers, amides or sulfoxides are preferred, and ethers (especially tetrahydrofuran) are more preferred.

The base used can be, for example, an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; an alkyllithium such as methyllithium, ethyllithium, butyllithium or sec-butyllithium; or an alkyllithium amide such as diiso Lithium propylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide or bis(trimethylsilyl)amide sodium. Preference is given to alkyllithium (especially butyllithium) or alkyllithium amide (especially lithium diisopropylamide).

The reaction temperature may vary depending on the raw materials and reagents, but is usually in the range of -100 to 30°C and preferably in the range of -70 to 0°C.

The reaction time may vary depending on the raw materials, reagents or reaction temperature, but is usually in the range of 5 minutes to 10 hours and preferably in the range of 10 minutes to 5 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, the solvent is removed by evaporation, or the solvent is removed by evaporation, water is added to the residue, a hydrophobic solvent (such as benzene, ether, ethyl acetate) is added to extract the compound, the extracted organic layer is washed with water, and The desired compound was isolated by drying over magnesium sulfate and distilling off the solvent. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

When the target compound in this step is used in the next step, no isolation or purification is required after the reaction is completed.

Method E is a synthesis method of the compound (XXVII) in which the substituent on the ring A of the intermediate compound (XVIII) in the method A contains a carbamoyl group and the compound (XXVIII) used as a starting material in the method F.

In step E1, the compound (XXVI) is prepared by reacting the compound (XXIV) with the compound of the general formula (XXV) in the presence of a base in an inert solvent. When X in compound (XXVI) is a sulfur atom, it is the starting compound (XXVIII) in method F.

The solvent used is not particularly limited so long as it does not interfere with the reaction and can dissolve a certain amount of the raw material. They can be, for example, aliphatic hydrocarbons such as hexane, heptane, petrolatum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorine Benzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diglyme; diamines such as N, N, N', N' - Tetramethylenediamine; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide or hexamethylphosphoramide; or sulfoxides such as dimethylsulfoxide or sulfolane . Amides or sulfoxides are preferred, and amides (especially dimethylformamide) are more preferred.

The base used may be, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; an alkali metal hydride such as lithium hydride, sodium hydride or Potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4,3,0]nonan-5- ene, 1,4-5 azabicyclo[2,2,2]octane (DABCO) or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU); alkyl Lithium such as methyllithium, ethyllithium or butyllithium; or lithium alkylamide such as lithium diisopropylamide or lithium dicyclohexylamide. Preference is given to alkali metal carbonates, alkali metal bicarbonates or alkali metal hydroxides, and more preferably alkali metal carbonates (in particular sodium carbonate, potassium carbonate or lithium carbonate).

The reaction temperature may vary depending on the raw materials and reagents, but is usually in the range of -10 to 100°C and preferably in the range of 0 to 50°C.

The reaction time may vary depending on the raw materials, reagents or reaction temperature, but is usually in the range of 30 minutes to 30 hours and preferably in the range of 1 to 20 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, the solvent is removed by evaporation, or the solvent is removed by evaporation, water is added to the residue, a hydrophobic solvent (such as benzene, ether, ethyl acetate) is added to extract the compound, the extracted organic layer is washed with water, and The desired compound was isolated by drying over magnesium sulfate and distilling off the solvent. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

In step E2, the compound (XXVII) is prepared by reacting the compound (XXVI) with ammonia gas or concentrated ammonia solution in an inert solvent. When X in compound (XXVII) is a sulfur atom, the substituent on ring A in compound (XVIII) contains a carbamoyl group.

The solvent used is not particularly limited so long as it does not interfere with the reaction and can dissolve a certain amount of the starting material. They can be, for example, aliphatic hydrocarbons such as hexane, heptane, petrolatum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorine benzene or dichlorobenzene; or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diglyme; alcohols such as methanol, ethanol, propanol, isopropyl Alcohols, butanol or isobutanol; diamines such as N,N,N',N'-tetramethylenediamine; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphine amides; or sulfoxides such as dimethylsulfoxide or sulfolane. Ether or alcohol is preferred, and alcohol (especially methanol or ethanol) is more preferred.

The reaction temperature may vary depending on the raw materials and reagents, but is usually in the range of -10 to 100°C and preferably in the range of 0 to 50°C.

The reaction time may vary depending on the raw materials, reagents or reaction temperature, but is usually in the range of 1 to 30 hours and preferably in the range of 3 to 20 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, the solvent is removed by evaporation, or the solvent is removed by evaporation, water is added to the residue, a hydrophobic solvent (such as benzene, ether, ethyl acetate) is added to extract the compound, the extracted organic layer is washed with water, and The desired compound was isolated by drying over magnesium sulfate and distilling off the solvent. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

In step E3, the compound (XXVII) can also be prepared by condensing the compound (XXIV) with ammonia in an inert solvent and can be prepared, for example, by the azide method, active ester method, mixed anhydride method or condensation method (preferably mixed Anhydride method) and other conventional peptide synthesis method conditions.

In the above-mentioned azide method, at a temperature of -10 to 100°C (preferably 0 to 50°C), in an inert solvent (such as an amide such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphorus The compound (XXIV) is treated with hydrazine in an amide, preferably dimethylformamide). The synthesized amino acid hydrazines are converted to azides by reaction with nitrite followed by treatment with ammonia.

The nitrite compound used may be, for example, an alkali metal nitrite such as sodium nitrite or an alkyl nitrite such as isoamyl nitrite.

The reaction is preferably carried out in an inert solvent, which may be an amide such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; a sulfoxide such as dimethyl sulfoxide or tetrahydro Thiophene sulfone; or a pyrrolidone such as N-methylpyrrolidone, preferably an amide (especially dimethylformamide).

Alternatively, step 2 (the azide-forming reaction and the reaction with ammonia) in this method can be performed in a one-pot process.

The reaction temperature may vary depending on the raw materials or reagents, but the reaction to form azide is usually carried out at -70 to 50°C (preferably -50 to 0°C), and the reaction with ammonia is carried out at -70°C. ~50°C (preferably -10~10°C) range.

The reaction time may vary depending on the raw materials, reagents or reaction time, but the reaction to form azide is generally carried out in the range of 5 minutes to 3 hours (preferably 10 minutes to 1 hour), while the reaction with ammonia is Over 5 hours and preferably in the range of 10 hours to 5 days.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, the solvent is removed by evaporation, or the solvent is removed by evaporation, water is added to the residue, a hydrophobic solvent (such as benzene, ether, ethyl acetate) is added to extract the compound, the extracted organic layer is washed with water, and The desired compound was isolated by drying over magnesium sulfate and distilling off the solvent. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

The active ester method is accomplished by treating the compound (XXIV) with an ester-forming reagent in an inert solvent and treating the synthesized active ester with ammonia in an inert solvent.

The solvent used in the two-step reaction is not particularly limited as long as it does not interfere with the reaction and can dissolve a certain amount of the starting material. They may be, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dichlorobenzene, methoxyethane or diglyme; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; or nitriles such as acetonitrile. Preference is given to ethers (especially tetrahydrofuran) or amides (especially dimethylformamide).

The active ester-forming reagent used can be, for example, an N-hydroxy compound such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboximide (dicarboximide ) or disulfides such as dipyridyl disulfides. The active esterification reaction is preferably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine.

The reaction temperature can vary according to the raw materials or reagents, but the active esterification reaction is usually carried out in the range of -70 to 150°C (preferably -10 to 100°C), and the reaction with ammonia is carried out at -20°C. It is carried out in the range of ~100°C (preferably 0-50°C).

The reaction time may vary depending on the raw materials, reagents or reaction time, but the two-step reaction is usually carried out in the range of 30 minutes to 80 hours (preferably 1 to 48 hours).

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, the solvent is removed by evaporation, or the solvent is removed by evaporation, water is added to the residue, a hydrophobic solvent (such as benzene, ether, ethyl acetate) is added to extract the compound, the extracted organic layer is washed with water, and The desired compound was isolated by drying over magnesium sulfate and distilling off the solvent. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

The mixed anhydride method is accomplished by treating the compound (XXIV) with a mixed anhydride in an inert solvent in the presence of a base and treating the resulting mixed anhydride with ammonia in an inert solvent.

The solvent used in the reaction of synthesizing the mixed acid anhydride is not particularly limited as long as it does not interfere with the reaction and can dissolve a certain amount of the raw material. They may be, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dichlorobenzene, methoxyethane or diglyme; or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide, and preferably ethers (especially tetrahydrofuran).

The mixed anhydride forming reagent may be, for example, a C ₁ -C ₄ -alkyl halocarbonate such as ethyl chlorocarbonate or isobutyl chlorocarbonate; a C ₁ -C ₅ alkanoyl halide such as pivaloyl chloride; or C ₁ -C ₄ alkyl cyanophosphate or C ₆ -C ₁₄ aryl cyanophosphate such as diethylcyanophosphate or diphenylcyanophosphate. Preference is given to C ₁ -C ₄ alkyl halocarbonates (especially isobutyl chlorocarbonate).

The base used can be, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; or an organic amine such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine , 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4,3,0]nonan-5 -ene, 1,4-diazabicyclo[2,2,2]octane (DABCO) or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU,), And organic amines (especially triethylamine) are preferred.

The reaction temperature of the reaction for preparing the mixed acid anhydride may vary depending on the raw materials or reagents, but is usually in the range of -50 to 100°C (preferably -10 to 50°C).

The reaction time of the reaction for preparing the mixed acid anhydride may vary depending on the raw materials, reagents or reaction temperature, but generally ranges from 5 minutes to 20 hours (preferably 10 minutes to 10 hours).

The solvent used in the reaction of the mixed acid anhydride and ammonia is not specifically limited as long as it does not interfere with the reaction and can dissolve a certain amount of the raw materials. They may be, for example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diglyme; or amides such as formamide, dimethylformamide, dimethylethyl ether, amides or hexamethylphosphoramide, and preferably ethers (especially tetrahydrofuran).

The reaction temperature of the reaction between the mixed acid anhydride and ammonia may vary depending on the raw materials or reagents, but is usually in the range of -30 to 100°C (preferably 0 to 80°C).

The reaction time for the reaction of the mixed acid anhydride with ammonia may vary depending on the raw materials, reagents or reaction time, but generally ranges from 5 minutes to 24 hours (preferably 10 minutes to 5 hours).

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, the solvent is removed by evaporation, or the solvent is removed by evaporation, water is added to the residue, a hydrophobic solvent (such as benzene, ether, ethyl acetate) is added to extract the compound, the extracted organic layer is washed with water, and The desired compound was isolated by drying over magnesium sulfate and distilling off the solvent. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

The condensation reaction is accomplished by directly treating the compound (XXIV) with ammonia in an inert solvent in the presence of a condensing agent.

The condensing agent used may be, for example, dicyclohexylcarbodiimide, carbonyldiimidazole or 1-methyl-2-chloropyridinium iodide-triethylamine, and is preferably dicyclohexylcarbodiimide.

This reaction can be carried out under similar reaction conditions as described above for the synthesis of active esters.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, the solvent is removed by evaporation, or the solvent is removed by evaporation, water is added to the residue, a hydrophobic solvent (such as benzene, ether, ethyl acetate) is added to extract the compound, the extracted organic layer is washed with water, and The desired compound was isolated by drying over magnesium sulfate and distilling off the solvent. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

Method F is another method for synthesizing said compound (XXIX) wherein ring A of intermediate compound (XVIII) in method A contains a trifluoromethyl group as a substituent.

In step F1, according to the method described in Chemistry Letters, 827 (1992), by combining the compound (XXVIII) with trifluorodihydrotetrabutylammonium (TBA ⁺ H ₂ F ₃ ^- ) and 1,3 in an inert solvent -Dibromo-5,5-dimethylhydantoin (DBH) reaction to synthesize the compound (XXIX).

The solvent used is not particularly limited so long as it does not interfere with the reaction and can dissolve a certain amount of the raw material. They may be, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Dimethoxyethane or diglyme, and preferably halogenated hydrocarbons (especially dichloromethane).

The reaction temperature may vary depending on the raw materials or reagents, but is usually in the range of -30 to 100°C and preferably in the range of 0 to 50°C.

The reaction time may vary depending on the raw materials, reagents or reaction temperature, but is usually in the range of 10 minutes to 5 hours and preferably in the range of 30 minutes to 3 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, the solvent is removed by evaporation, water is added to the reaction mixture, a hydrophobic solvent (such as benzene, diethyl ether, ethyl acetate) is added to extract the compound, the extract is washed with water, dried over anhydrous magnesium sulfate and the solvent is evaporated , to isolate the target compound. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

Method G is another method for synthesizing said compound (XXXI) in which ring A of intermediate compound (XVIII) in method A contains a cyano group as a substituent.

In step G1, the compound (XXXI) is prepared by reacting the compound (XXX) with a dehydrating agent in an inert solvent.

The solvent used is not particularly limited so long as it does not interfere with the reaction and can dissolve a certain amount of the raw material. They can be, for example, aliphatic hydrocarbons such as hexane, heptane, petrolatum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorine benzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diglyme; esters such as methyl acetate or ethyl acetate; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide or hexamethylphosphoric triamide; or sulfoxides such as dimethylsulfoxide or sulfolane. Ethers, amides or sulfoxides are preferred, and amides (especially dimethylformamide) are more preferred.

The dehydrating agent used may be, for example, phosphorus oxychloride, trifluoroacetic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride or phosphorus pentoxide, and phosphorus oxychloride is preferred.

The reaction temperature may vary depending on the raw materials or reagents, but is usually in the range of -30 to 100°C and preferably in the range of -10 to 30°C.

The reaction time may vary depending on the raw materials, reagents or reaction temperature, but is usually in the range of 5 minutes to 10 hours and preferably in the range of 10 minutes to 3 hours.

After the reaction is completed, the target compound of this step is isolated from the reaction mixture in a conventional manner. For example, the solvent is removed by evaporation, water is added to the reaction mixture, a hydrophobic solvent (such as benzene, diethyl ether, ethyl acetate) is added to extract the compound, the extract is washed with water, dried over anhydrous magnesium sulfate and the solvent is evaporated , to isolate the target compound. The obtained object compound can be purified by recrystallization, reprecipitation or chromatography, if necessary.

The compound (II) as a monoamine oxidase inhibitor is a known compound, or by reacting the compound (XVI) with the compound of the following general formula as described in step A4, and, if necessary, removing the compound as described in step 5 Amino or alkylamino protecting group is synthesized,

HX-(CH ₂ ) _n -R ⁴ _a

(XVIIb) wherein X is as described above, R ⁴ _a is the same as R ² _a except that its amino group and mono C ₁ -C ₄ alkylamino group are protected,

In addition, the compound having an oxygen atom on X in the compound (II) can be obtained by reacting the compound (XVI) with the compound of the following general formula as described in step B1, and, if necessary, as described in step A5 It is synthesized by removing the amino or alkylamino protecting group,

Y-(CH ₂ ) _n -R ⁴ _a

(XVIIc) wherein R ⁴ _a and Y are as described above.

Because the isoxazole derivatives (I) and (II) of the present invention have significant inhibitory effects on B-type and A-type monoamine oxidase (the inhibitory effect on B-type monoamine oxidase is particularly significant), they can be used for Parkinson's disease, depression and Alzheimer's disease (particularly Parkinson's disease) therapeutic or preventive agent, and has low toxicity.

[Best Embodiment of the Invention]

The invention is described in more detail in the following sections of Examples, Formulations and Test Methods, but the invention is not limited to these Examples. Example 13-(2-aminoethoxy)-5-chloro-1,2-benzisoxazole hydrochloride (a) ethyl 5-chlorosalicylate

Under stirring at room temperature, concentrated sulfuric acid (40 ml) was added to a suspension of 5-chlorosalicylic acid (500 g) in ethanol (2 L). After the reaction mixture was refluxed for 12 hours, the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% NaCl solution and 4% sodium bicarbonate solution, then evaporated under reduced pressure and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (514 g, 88%) as a pale yellow oil.

IR spectrum (KBr) v _max cm ^-1 : 1680, 1475

NMR spectrum (DMSO-d ₆ ) δppm: 1.42 (3H, t, J=7.3Hz),

4.43 (2H, q, J = 7.3Hz), 6.93 (1H, d, J = 7.3Hz), 7.35 (1H, dd, J = 7.3Hz, J = 2.5Hz),

7.82 (1H, d, J=2.5Hz), 11.80 (1H, s). (b) 5-chloro salicylcarbohydroxamic acid (salicylcarbohydroxamic acid)

Hydroxylamine hydrochloride (197g) was dissolved in water (400ml) and cooled to 5°C. A methanol (1.5 L) solution of potassium hydroxide (545 g) was added, and a methanol (400 ml) solution of ethyl 5-chlorosalicylate (500 g) was added dropwise with stirring at the same temperature. After stirring at 5-10°C for 30 minutes, stirring was continued at room temperature for 3 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in ice water (6 L). The pH of the solution was adjusted to 2 with concentrated hydrochloric acid, and the precipitated crystals were filtered and washed with water to obtain the title compound (438 g, 93%) as colorless crystals.

Melting point: 216-222°C

IR spectrum (KBr) v _max cm ^-1 : 3127, 1618, 1577, 1523, 1492, 1413;

NMR spectrum (DMSO-d ₆ ) δppm: 6.96 (1H, d, J = 7.3 Hz),

7.43(1H, dd, J=7.3Hz, J=2.5Hz), 9.31-9.52(1H, brs), 10.88-11.03(1H, brs),

11.66-11.87(1H, brs).(c) 5-Chloro-3-hydroxy-1,2-benzisoxazole

Thionyl chloride (100ml) was added dropwise to a solution of 5-chlorosalicylcarboxyxamic acid (216g) in tetrahydrofuran (600ml) under stirring at 10-20°C. After stirring at the same temperature for 2 hours, the reaction mixture was evaporated under reduced pressure, and the residue was dissolved in dioxane (600ml) and cooled to 0-5°C. Triethylamine (383ml) was added to the reaction mixture and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and ice water (3 L) was added to the residue. The pH of the mixture was adjusted to 2 with concentrated hydrochloric acid, and the precipitated crystals were filtered and washed with water. Recrystallization from ethyl acetate gave the title compound (172 g, 88%) as colorless needle crystals.

Melting point: 219-222°C

IR spectrum (KBr) v _max cm ^-1 : 3400-2000, 1613, 1560, 1516;

NMR spectrum (DMSO-d ₆ ) δppm: 7.43-7.72 (2H, m), 7.82 (1H, d, J=2.5Hz),

10.78-11.02 (1H, brs). (d) 2-(N-tert-butoxycarbonylamino)ethanol

To a solution of 2-aminoethanol (6.1 g) in tetrahydrofuran and water (1:1, 100 ml) was added di-tert-butyl dicarbonate (21.8 g) under ice-cooling and stirring. The reaction mixture was stirred at the same temperature for 1 hour and then at room temperature for 5 hours. Ethyl acetate (200 ml) was added to the reaction mixture, washed with water, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (15.3 g) as a colorless oil.

RF: (cyclohexane: ethyl acetate = 1: 1): 0.35;

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 2.35-2.50 (1H, brs),

3.29 (2H, q, J = 5.3Hz), 3.71 (2H, q, J = 5.3Hz), 4.85-5.05 (1H, brs). (e) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloro-1,2-benzisoxazole

To a solution of triphenylphosphine (0.87 g) in tetrahydrofuran (10 ml) was added dropwise diethyl azodicarboxylate (0.57 g) under ice-cooling and stirring. The reaction mixture was stirred at the same temperature for 10 minutes, and then 2-(N-tert-butoxycarbonylamino)ethanol (0.48 g) and 5-chloro-3-hydroxy-1,2-benziso Oxazole (0.51 g), stirred under ice-cooling for 10 minutes and at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, using cyclohexane/ethyl acetate (4/1) as eluent, and recrystallized from isopropanol to obtain the title compound (0.70 g).

Melting point: 106-107°C

IR spectrum (KBr) v _max cm ^-1 : 3376, 1706, 1611, 1541, 1525;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.64 (2H, q, J=5.1Hz),

4.50(2H, T, J=5.1Hz), 4.95(1H, brs), 7.37(1H, d, J=8.8Hz),

7.49 (1H, dd, J=8.8Hz, J=2.0Hz), 7.63 (1H, d, J=2.0Hz).(f) 3-(2-Aminoethoxy)-5-chloro-1,2 -Benzisoxazole hydrochloride

To 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloro-1,2-benzisoxazole (0.50 g) was added 4N-hydrochloric acid/1,4-dioxane solution (4.0ml) and stirred at room temperature for 15 minutes. The precipitated crystals were filtered and washed with 1,4-dioxane to obtain the title compound (0.38 g) as colorless crystals.

Melting point: 217-221°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1612, 1534, 1519;

NMR spectrum (DMSO-d ₆ ) δppm: 3.33 (2H, t, J=5.1Hz), 4.61 (2H, t, J=5.1Hz),

7.73 (2H, d, J = 1.4Hz), 7.88 (1H, d, J = 1.4Hz), 8.28 (3H, brs). Example 23-(2-aminoethoxy)-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-1,2 -Benzisoxazole

The title compound was obtained from 3-hydroxyl-1,2-benzisoxazole and 2-(N-tert-butoxycarbonylamino)ethanol by reacting and treating in a similar manner as described in Example 1(e), The yield was 68%.

Melting point: 106-107°C

IR spectrum (KBr) v _max cm ^-1 : 3326, 1716, 1707, 1615, 1536;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.65 (2H, q, J=5.1Hz),

4.51 (2H, t, J = 5.1 Hz), 4.90-5.05 (1H, brs), 7.26-7.66 (4H, m). (b) 3-(2-aminoethoxy)-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 1(f), the title compound was obtained from 3-(2-(N-tert-butoxycarbonylamino)ethoxy-1,2-benzisoxazole , the yield was 98%.

Melting point: 194-197°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1614, 1541, 1521;

NMR spectrum (D ₂ O) δppm: 3.60 (2H, t, J = 5.1 Hz), 4.94 (2H, t, J = 5.1 Hz),

7.41-7.80 (4H, m). Example 33-(3-aminopropoxy)-1,2-benzisoxazole hydrochloride (a) 3-(N-tert-butoxycarbonylamino)propanol

The title compound (1.65 g) was obtained from 3-aminopropanol (0.75 g) and di-tert-butyl dicarbonate (2.18) by reacting and working up in a manner similar to that described in Example 1(d).

Rf (cyclohexane: ethyl acetate = 1: 1): 0.35;

NMR spectrum (CDCl ₃ ) δppm: 1.49 (9H, s), 1.70 (2H, q, J=5.9Hz),

2.85-2.95 (1H, brs), 3.33 (2H, q, J=5.9Hz), 3.70 (2H, q, J=5.9Hz),

4.65-4.90(1H, brs).(b) 3-(3-(N-tert-butoxycarbonylamino)propoxy)-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 1 (e), the title compound was obtained from 3-hydroxyl-1,2-benzisoxazole and 3-(N-tert-butoxycarbonylamino)propanol , the yield was 75%.

Melting point: 59-60°C

IR spectrum (KBr) v _max cm ^-1 : 3383, 1690, 1613, 1539, 1521;

NMR spectrum (CDCl ₃ ) δppm: 1.44 (9H, s), 2.05-2.13 (2H, m),

3.36(2H, q, J=6.3Hz), 4.52(2H, t, J=5.9Hz), 4.70-4.85(1H, brs),

7.25-7.65(4H, m).(c) 3-(3-aminopropoxy)-1,2-benzisoxazole hydrochloride

According to the reaction and treatment similar to that described in Example 1(f), the title was prepared from 3-(3-(N-tert-butoxycarbonylamino)propoxy)-1,2-benzisoxazole Compound, the yield was 96%.

Melting point: 146-147°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1615, 1541, 1536;

NMR spectrum (D ₂ O) δppm: 2.29-2.36 (2H, m), 3.31 (2H, t, J=7.3Hz),

4.59 (2H, t, J=5.9Hz), 7.40-7.78 (4H, m). Example 43-(4-aminobutoxy)-1,2-benzisoxazole hydrochloride (a) 4-(N-tert-butoxycarbonylamino)butanol

The title compound (1.80 g) was prepared from 4-aminobutanol (0.89 g) and di-tert-butyl dicarbonate (2.18) by reacting and working up in a manner similar to that described in Example 1(d).

Rf (cyclohexane: ethyl acetate = 1: 1): 0.35;

NMR spectrum (CDCl ₃ ) δppm: 1.44 (9H, s), 1.55-1.65 (4H, m),

3.16 (2H, q, J = 5.9Hz), 3.67 (2H, q, J = 5.9Hz), 4.55-4.75 (1H, brs). (b) 3-(4-(N-tert-butoxycarbonylamino)butoxy)-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 1 (e), the title compound was obtained from 3-hydroxyl-1,2-benzisoxazole and 4-(N-tert-butoxycarbonylamino)butanol , the yield was 71%.

IR spectrum (KBr) v _max cm ^-1 : 3321, 1701, 1615, 1539, 1509;

NMR spectrum (CDCl ₃ ) δppm: 1.14 (9H, s), 1.62-1.74 (2H, m),

1.91-1.97(2H, m), 3.15-3.27(2H, brs), 4.46(2H, t, J=6.5Hz), 4.55-4.70(1H, brs),

7.24-7.66 (4H, m). (c) 3-(4-aminobutoxy)-1,2-benzisoxazole hydrochloride

According to the reaction and treatment similar to that described in Example 1(f), the title was prepared from 3-(4-(N-tert-butoxycarbonylamino)butoxy)-1,2-benzisoxazole Compound, the yield is 97%.

Melting point: 138-139°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1613, 1541;

NMR spectrum (D ₂ O) δppm: 1.88-1.97 (2H, m), 1.99-2.06 (2H, m),

3.14 (2H, t, J = 7.6Hz), 4.50 (2H, t, J = 6.1Hz), 7.39-7.78 (4H, m). Example 5 3-(2-aminoethoxy)-5-fluoro-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy) -5-fluoro-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 1 (e), the obtained compound was prepared from 5-fluoro-3-hydroxyl-1,2-benzisoxazole and 2-(N-tert-butoxycarbonylamino)ethanol The title compound was obtained in a yield of 60%.

IR spectrum (KBr) v _max cm ^-1 : 3338, 1707, 1623, 1543, 1534, 1504;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.64 (2H, q, J=5.1Hz),

4.50 (2H, t, J = 5.1 Hz), 4.88-5.03 (1H, brs), 7.22-7.42 (3H, m). (b) 3-(2-aminoethoxy)-5-fluoro-1,2-benzisoxazole hydrochloride

According to the reaction and treatment similar to that described in Example 1(f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-fluoro-1,2-benzisoxazole The title compound was obtained in 98% yield.

Melting point: 209-211°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1621, 1606, 1538, 1505;

NMR spectrum (D ₂ O) δppm: 3.59 (2H, t, J = 5.1 Hz), 4.73 (2H, t, J = 5.1 Hz),

7.42-7.58 (3H, m). Example 63-(2-aminoethoxy)-5-methoxy-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy base)-5-methoxy-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 1 (e), it is prepared from 3-hydroxy-5-methoxy-1,2-benzisoxazole and 2-(N-tert-butoxycarbonylamino)ethanol The title compound was obtained in 74% yield.

IR spectrum (KBr) v _max cm ^-1 : 3255, 1698, 1615, 1540, 1508;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.65 (2H, q, J=5.1Hz), 3.86 (3H, s),

4.50(2H, t, J=5.1Hz), 4.90-5.05(1H, brs), 6.98(1H, d, J=2.6Hz),

7.15 (1H, dd, J=9.2Hz, J=2.6Hz), 7.33 (1H, d, J=9.2Hz). (b) 3-(2-aminoethoxy)-5-methoxy-1 , 2-Benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-methoxy-1,2-benzoisoxane Azole was used to obtain the title compound in 96% yield.

Melting point: 210-212°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1606, 1538, 1521, 1505;

NMR spectrum (D ₂ O) δppm: 3.59 (2H, t, J=5.1 Hz), 3.90 (3H, s),

4.71 (2H, t, J = 5.1Hz), 7.22 (1H, d, J = 2.6Hz), 7.32 (1H, dd, J = 9.2Hz, J = 2.6Hz),

7.48 (1H, d, J=9.2Hz). Example 7 3-(2-aminoethoxy)-5-methyl-1,2-benzisoxazole hydrochloride (a) 5-methyl water ethyl sylate

Following the reaction and treatment similar to that described in Example 1(a), the title compound was prepared from 5-methylsalicylic acid in a yield of 84%. (b) 5-methyl salicyl carboxylic acid

Following the reaction and treatment similar to that described in Example 1(b), the title compound was prepared from ethyl 5-methylsalicylate in a yield of 94%.

Melting point: 172-175°C (decomposition);

NMR spectrum (DMSO-d ₆ ) δppm: 2.22 (3H, s), 6.78 (1H, d, J=8.6Hz),

7.17 (1H, d, J=8.6Hz), 7.50 (1H, s), 9.25 (1H, s), 11.33 (1H, s), 11.95 (1H, s). (c) 3-Hydroxy-5-methyl-1,2-benzisoxazole

Following the reaction and treatment similar to that described in Example 1(c), the title compound was prepared from 5-methylsalicylcarboxyxamic acid in a yield of 94%.

Melting point: 95-97°C;

NMR spectrum (CDCl ₃ ) δppm: 2.45 (3H, s), 7.13-7.43 (3H, m),

9.02-9.15 (1H, brs). (d) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-methyl-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 1 (e), it is prepared from 3-hydroxy-5-methyl-1,2-benzisoxazole and 2-(N-tert-butoxycarbonylamino)ethanol The yield of the title compound was 69%.

IR spectrum (KBr) v _max cm ^-1 : 3367, 1717, 1614, 1538-1522;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 2.45 (3H, s), 3.64 (2H, q, J=5.1Hz),

4.50 (2H, t, J=5.1Hz), 4.90-5.05 (1H, brs), 7.31-7.52 (3H, m). (e) 3-(2-aminoethoxy)-5-methyl-1 , 2-Benzisoxazole hydrochloride

React and handle according to the similar method described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino) ethoxy)-5-methyl-1,2-benzisoxazole The title compound was obtained in 97% yield.

Melting point: 218-220°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1625, 1612, 1536, 1502;

NMR spectrum (DMSO-d ₆ ) δppm: 2.43 (3H, s), 3.26-3.41 (3H, m),

4.60 (2H, t, J=5.1Hz), 7.48-7.55 (3H, m), 8.32 (3H, brs) Example 83-(2-aminoethoxy)-5-nitro-1,2-benzene And isoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-nitro-1,2-benzisoxazole

React according to the similar method described in embodiment 1 (e) (continue to react for 3 hours) and process, by 3-hydroxyl-5-nitro-1,2-benzisoxazole and 2-(N-tert-butyl Oxycarbonylamino)ethanol to obtain the title compound in 74% yield.

Melting point: 136-137°C;

IR spectrum (KBr) v _max cm ^-1 : 3346, 1688, 1624, 1555, 1531;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.67 (2H, q, J=5.1Hz),

4.55(2H, t, J=5.1Hz), 4.87-5.05(1H, brs), 7.56(1H, d.J=9.2Hz),

8.46 (1H, dd, J=9.2Hz, J=2.2Hz), 8.62 (1H, d, J=2.2Hz). (b) 3-(2-aminoethoxy)-5-nitro-1, 2-Benzisoxazole hydrochloride

React and handle according to the similar method described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino) ethoxy)-5-nitro-1,2-benzisoxazole The title compound was obtained in 99% yield.

Melting point: 228-231°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1620, 1543, 1519;

NMR spectrum (DMSO-d ₆ ) 6ppm: 3.36 (2H, t, J = 5.1 Hz), 4.66 (2H, t, J = 5.1 Hz),

7.93 (2H, d, J = 9.2Hz), 8.34 (3 H, brs), 8.54 (1H, dd, J = 9.2Hz, J = 2.2Hz),

8.74 (1H, d, J=2.2Hz). Example 9 3-(2-aminoethoxy)-7-chloro-1,2-benzisoxazole hydrochloride (a) 3-(2-( N-tert-butoxycarbonylamino)ethoxy)-7-chloro-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 1 (e), the obtained compound was prepared from 3-hydroxyl-7-chloro-1,2-benzisoxazole and 2-(N-tert-butoxycarbonylamino)ethanol The title compound was obtained in a yield of 62%.

Melting point: 64-65°C;

IR spectrum (KBr) v _max cm ^-1 : 3355, 1714, 1690, 1615, 1556, 1538;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.65 (2H, q, J=5.1Hz),

4.53(2H, t, J=5.1Hz), 4.87-5.03(1H, brs), 7.23(1H, dd, J=8.0Hz, J=8.0Hz),

7.52-7.58(2H, m).(b) 3-(2-aminoethoxy)-7-chloro-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 1 (f), prepared from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-chloro-1,2-benzisoxazole The title compound was obtained in 98% yield.

Melting point: 198-200°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1616, 1599, 1541, 1516;

NMR spectrum (DMSO-d ₆ ) δppm: 3.35 (2H, t, J=5.1Hz), 4.65 (2H, t, J=5.1Hz),

7.44 (1H, dd, J = 8.0Hz, J = 8.0Hz), 7.79 (1H, d, J = 8.0Hz), 7.83 (1H, d, J = 8.0Hz),

8.34 (3H, brs). Example 10 3-(2-aminoethoxy)pyrido[3,2-d]isoxazole hydrochloride and 3-(2-aminoethoxy)pyrido[3,2-d]isoxazole Dihydrochloride (a) methyl 2-chloronicotinate

To a suspension of 2-chloronicotinic acid (15.75 g) in ethyl acetate (200 ml) was added excess diazomethane (diethyl ether solution) under stirring at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes, the solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate, and activated carbon was added. The mixture was filtered and evaporated under reduced pressure to give the title compound (15.5 g). (b) 2-chloropyridine-3-carboxylic acid (carbohydroxamic acid)

Under ice-cooling and stirring, sodium hydroxide solution (7.65 g of sodium hydroxide in 50 ml) was added to a solution of hydroxylamine hydrochloride (6.75 g) in water (25 ml), and 2-chlorohydrin was added to the stirred solution. Methanol solution of methyl nicotinate (15.5 g). After stirring at room temperature for 2.5 hours, the pH was adjusted to 3.5 with 6N-hydrochloric acid under ice cooling. After 1 hour, the precipitated crystals were filtered and washed with water, and then with methanol-ether mixture (1:1) to obtain the The title compound (11.0 g).

Melting point: 179°C;

IR spectrum (liquid paraffin) v _max cm ^-1 : 3154, 1645, 1580;

NMR spectrum (DMSO-d ₆ ) δppm: 7.34 (1H, dd, J=7.5Hz, J=5.0Hz),

7.80(1H, dd, J=7.5Hz, 2.0Hz), 8.42(1H,dd, J=5.0Hz, J=2.0Hz), 9.30(1H, s), 11.00Hz(1H, s).(c) 3-Hydroxypyrido[3,2-d]isoxazole

To 10% aqueous sodium hydroxide solution (26 ml) was added 2-chloropyridine-3-carboxyxamic acid (2.60 g) and refluxed for 30 minutes. After adjusting the pH to 2.0 with 6N-hydrochloric acid under ice-cooling, the reaction mixture was allowed to stand at room temperature for 30 minutes. The precipitated crystals were filtered and washed with water and then with a methanol-ether mixture (1:1) to give the title compound (1.68 g).

Melting point: 258°C;

IR spectrum (liquid paraffin) v _max cm ^-1 : 2750-2050, 1620, 1600;

NMR spectrum (DMSO-d ₆ ) δppm: 7.40 (1H, dd, J=8.0Hz, J=5.0Hz),

8.40-8.70 (2H, m). (d) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)pyrido[3,2-d]isoxazole

The title was prepared from 3-hydroxypyrido[3,2-d]isoxazole and 2-(N-tert-butoxycarbonylamino)ethanol by reacting and working up in a manner similar to that described in Example 1(e). Compound, the yield is 61%.

Melting point: 127-128°C;

IR spectrum (KBr) v _max cm ^-1 : 3335, 1716, 1707, 1615, 1605, 1537;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.65 (2H, q, J=5.1Hz),

4.54(2H, t, J5.1Hz), 4.85-5.05(1H, brs), 7.31(1H, dd, J=7.9Hz, J=4.6Hz),

8.06 (1H, dd, J=7.9Hz, J=1.5Hz), 8.61 (1H, dd, J=4.6Hz, J=1.5Hz).(e) 3-(2-Aminoethoxy)pyrido[ 3,2-d]isoxazole dihydrochloride

According to the similar reaction and treatment described in Example 1 (f), the obtained compound was obtained from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)pyrido[3,2-d]isoxazole The title compound was obtained with a yield of 99%.

Melting point: 204-210°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1606, 1538, 1508;

NMR spectrum (DMSO-d ₆ ) δppm: 3.35 (2H, td, J=5.1Hz, J=5.1Hz),

4.65 (2H, t, J=5.1Hz), 7.54 (1H, dd, J=7.9Hz, J=4.6Hz),

8.34(1H, dd, J=7.9Hz, J=1.5Hz), 8.34(3H, brs),

8.70 (1H, dd, J=4.6Hz, J=1.5Hz). (f) 3-(2-Aminoethoxy)pyrido[3,2-d]isoxazole hydrochloride

Under ice-cooling and stirring, to a solution of 3-(2-aminoethoxy)pyrido[3,2-d]isoxazole dihydrochloride in water (10ml) was added 1N aqueous sodium hydroxide solution (16ml) , and the mixture was stirred at the same temperature for 5 minutes. The reaction mixture was evaporated under reduced pressure and recrystallized from a methanol-water mixture (1:1) to give the title compound (3.2 g, 94%) as colorless crystals.

Melting point: 210-213°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3012, 3003, 2968, 2899, 2845, 2803, 2752,

1636, 1615, 1606, 1538, 1509;

NMR spectrum (DMSO-d ₆ ) δppm: 3.35 (2H, t, J=5.1Hz), 4.65 (2H, t, J=5.1Hz),

7.54(1H, dd, J=7.9Hz, J=4.6Hz), 8.34(1H,dd, J=7.9Hz, J=1.5Hz),

8.36 (3H, brs), 8.70 (1H, dd, J=4.6Hz, J=1.5Hz). Example 113-(2-aminoethoxy)-6-chloro-1,2-benzisoxazole Hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-6-chloro-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 1 (e), the obtained compound was prepared from 3-hydroxy-6-chloro-1,2-benzisoxazole and 2-(N-tert-butoxycarbonylamino)ethanol The title compound was obtained in a yield of 60%.

Melting point: 95-96°C;

IR spectrum (KBr) v _max cm ^-1 : 3398, 1698, 1614, 1541, 1519;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.64 (2H, q, J=5.1Hz),

4.50(2H, t, J=5.Hz), 4 88-5.02(1H, brs), 7.27(1H, dd, J=8.4Hz, J=1.5Hz),

7.47 (1H, d, J=1.5Hz), 7.55 (1H, d, J=8.4Hz). (b) 3-(2-aminoethoxy)-6-chloro-1,2-benzoisoxane azole hydrochloride

Reaction and treatment according to the similar method described in Example 1 (f), prepared from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-6-chloro-1,2-benzisoxazole The title compound was obtained in 97% yield.

Melting point: 198-202°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1612, 1537;

NMR spectrum (DMSO-d ₆ ) δppm: 3.34 (2H, t, J=5.1Hz), 4.62 (2H, t, J=5.1Hz),

7.48 (1H, dd, J = 8.4Hz, J = 1.5Hz), 7.81 (1H, d, J = 8.4Hz), 7.92 (1H, d, J = 1.5Hz),

8.36(3H, brs). Example 12 3-(2-aminoethoxy)-5,7-dichloro-1,2-benzisoxazole hydrochloride (a) 3-(2-(N- tert-butoxycarbonylamino)ethoxy)-5,7-dichloro-1,2-benzisoxazole

React and handle according to the similar method described in Example 1 (e), from 3-hydroxyl-5,7-dichloro-1,2-benzisoxazole and 2-(N-tert-butoxycarbonylamino)ethanol The title compound was obtained in 68% yield.

Melting point: 94-95°C;

IR spectrum (KBr) v _max cm ^-1 : 3359, 1678, 1542, 1524;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.64 (2H, q, J=5.1Hz),

4.51 (2H, t, J = 5.1Hz), 4.85-5.00 (1H, brs), 7.54 (2H, d, J = 1.0Hz). (b) 3-(2-Aminoethoxy)-5,7 -Dichloro-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5,7-dichloro-1,2-benzoiso Oxazole afforded the title compound in 92% yield.

Melting point: 198-203°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1600, 1541, 1514;

NMR spectrum (DMSO-d ₆ ) δppm: 3.34 (2H, t, J=5.1Hz), 4.63 (2H, t, J=5.1Hz),

7.91 (1H, d, J=2.0Hz), 8.03 (1H, d-J=2.0Hz), 8.31 (3H, brs). Example 133-(2-Aminoethoxy)-7-methyl-1,2 -Benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-methyl-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 1 (e), it is prepared from 3-hydroxy-7-methyl-1,2-benzisoxazole and 2-(N-tert-butoxycarbonylamino)ethanol The yield of the title compound was 66%.

Melting point: 54-55°C;

IR spectrum (KBr) v _max cm ^-1 : 3332, 1713, 1699, 1615, 1539, 1506;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 2.51 (3H, s). 3.65 (2H, q, J=5.1Hz),

4.51 (2H, t, J=5.1Hz), 4.90-5.06 (1H, brs), 7.15-7.47 (3H, m). (b) 3-(2-aminoethoxy)-7-methyl-1 , 2-Benzisoxazole Hydrochloride

Reaction and treatment according to the similar method described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino) ethoxy)-7-methyl-1,2-benzisoxazole The title compound was obtained in 96% yield.

Melting point: 195-197°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1614, 1545, 1520, 1505;

NMR spectrum (DMSO-d ₆ ) δppm: 2.47 (3H, s), 3.34 (2H, t, J=5.1Hz),

4.62 (2H, t, J = 5.1 Hz), 7.28-7.61 (3H, m). Example 14 3-(2-aminoethoxy)-6-methyl-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy )-6-methyl-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 1 (e), it is prepared from 3-hydroxy-6-methyl-1,2-benzisoxazole and 2-(N-tert-butoxycarbonylamino)ethanol The yield of the title compound was 64%.

Melting point: 128-129°C;

IR spectrum (KBr) v _max cm ^-1 : 3331, 1718, 1708, 1629, 1613, 1534;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 2.50 (3H, s), 3.65 (2H, q, J=5.1Hz),

4.49(2H, t, J=5.1Hz), 4.90-5.05(1H, brs), 7.10(1H, d, J=8.0Hz), 7.23(1H, s),

7.50 (1H, d, J=8.0Hz). (b) 3-(2-aminoethoxy)-6-methyl-1,2-benzisoxazole hydrochloride

React and handle according to the similar method described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino) ethoxy)-6-methyl-1,2-benzisoxazole The title compound was obtained in 92% yield.

Melting point: 207-212°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1618, 1600, 1533;

NMR spectrum (DMSO-d ₆ ) δppm: 2.48 (3H, s), 3.33 (2H, t, J=5.1Hz),

4.59 (2H, t, J = 5.1Hz), 7.23 (1H, d, J = 8.0Hz), 7.46 (1H, s), 7.65 (1H, d, J = 8.0Hz),

8.33(3H, brs). Example 15 3-(2-aminoethoxy)-5-bromo-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxy Carbonylamino)ethoxy)-5-bromo-1,2-benzisoxazole

According to the reaction and treatment of the similar method described in Example 1 (e), the obtained compound was prepared from 3-hydroxy-5-bromo-1,2-benzisoxazole and 2-(N-tert-butoxycarbonylamino)ethanol The title compound was obtained in a yield of 67%.

Melting point: 123-124°C;

IR spectrum (KBr) v _max cm ^-1 : 3313, 1699, 1683, 1611, 1545;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.64 (2H, q, J=5.1Hz),

4.50(2H, t, J=5.1Hz), 4.85-5.00(1H, brs), 7.33(1H, d, J=8.9Hz),

7.62 (1H, dd, J=8.9Hz, J=1.9Hz), 7.80 (1H, d, J=1.9Hz). (b) 3-(2-aminoethoxy)-5-bromo-1,2 -Benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 1 (f), prepared from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-bromo-1,2-benzisoxazole The title compound was obtained in 95% yield.

Melting point: 220-224°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1611, 1535, 1516;

NMR spectrum (DMSO-d ₆ ) δppm: 3.38 (2H, t, J=5.1Hz), 4.61 (2H, t, J=5.1Hz),

7.67 (1H, d, J = 8.9Hz), 7.83 (1H, dd, J = 8.9Hz, J = 1.9Hz), 8.02 (1H, d, J = 1.9Hz),

8.25(3H, brs). Example 16 3,5-dichloro-1,2-benzisoxazole

With stirring at room temperature, pyridine (48ml) was added dropwise to a suspension of 5-chloro-3-hydroxyl-1,2-benzisoxazole (100g) in phosphorus oxychloride (80ml) within 1 hour, and then the mixture was refluxed for 5 Hour. The reaction mixture was added to ice water (500ml) and extracted with ethyl acetate, and the combined extracts were dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from petroleum ether to obtain the title compound (102 g, 92%) as colorless needles.

Melting point: 43-44°C;

IR spectrum (KBr) v _max cm ^-1 : 1648, 1419, 1285;

NMR spectrum (CDCl ₃ ) δppm: 7.59 (2H, d, J=1.5Hz), 7.70 (1H, brs). Example 17 3-(2-aminoethoxy)-5-fluoro-4-methyl-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino )ethoxy)-5-fluoro-1,2-benzisoxazole

To a solution of triphenylphosphine (0.87 g) in tetrahydrofuran (20 ml) was added diethyl azodicarboxylate (0.57 g) at 5°C and the mixture was stirred at the same temperature for 15 minutes. Then 5-fluoro-3-hydroxy-1,2-benzisoxazole (0.46 g) was added and the mixture was stirred at the same temperature for 15 minutes, then N-tert-butoxycarbonylethanolamine (0.48 g) was added and stirred at room temperature Stirring was continued for 24 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (9/1) as eluent to obtain the title compound (0.53 g, 60%) as a colorless powder.

Melting point: 104-105°C;

IR spectrum (KBr) v _max cm ^-1 : 3338, 1707, 1623, 1543, 1534, 1504;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.64 (2H, q, J=5.1Hz),

4.50(2H, t, J=5.1Hz), 4.95(1H, brs), 7.22-7.42(3H, m).b) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5 -Fluoro-4-methyl-1,2-benzisoxazole

3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-fluoro-1,2-benzisoxazole (0.27g) in tetrahydrofuran ( Lithium diisopropylamide (1.1 ml, 1.5 M solution in cyclohexane) was added dropwise to the solution (10 ml), and the mixture was stirred at the same temperature for 15 minutes before adding iodomethane (0.13 g). After stirring at -70°C for 15 minutes, the temperature was allowed to rise to 0°C. The reaction mixture was poured into ice water (40 ml), extracted twice with ethyl acetate (40 ml each), and the combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (9/1) as the eluent to obtain the title compound as a colorless powder (0.22 g, yield 94%) .

Melting point: 124-127°C;

IR spectrum (KBr) v _max cm ^-1 : 3353, 1688, 1539, 1505;

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 2.50 (3H, d, J=2.0Hz),

3.65(2H, q, J=5.1Hz), 4.49(2H, t, J=5.1Hz), 4.88(1H, brs), 7.15-7.30(2H, m).(c) 3-(2-Aminoethyl Oxy)-5-fluoro-4-methyl-1,2-benzisoxazole hydrochloride

3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-fluoro-4-methyl-1,2-benzisoxazole (0.15 g) was dissolved in 4N hydrochloric acid/dioxane solution (1.4ml) and stirred for 15 minutes. The reaction mixture was evaporated under reduced pressure and the precipitated crystals were filtered. The crystals were washed with ethyl acetate (3 ml) to obtain the title compound (0.13 g, yield 98%) as a colorless powder.

Melting point: 213-215°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1630, 1583, 1537, 1505;

NMR spectrum (DMSO-d ₆ ) δppm: 2.51 (3H, d, J=2.0Hz), 3.34 (2H, q, J=5.1Hz),

4.62 (2H, t, J=5.1Hz), 7.45-7.55 (2H, m), 8.33 (3H, brs). Example 183-(2-aminoethoxy)-4-carbamoyl-5-fluoro -1,2-Benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-carboxy-5-fluoro-1,2-benzisoxazole Oxazole

Under a nitrogen atmosphere at -70°C, add 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-fluoro-1,2-benzisoxazole (0.30g) to tetrahydrofuran (20ml) Lithium diisopropylamide (1.4 ml, 1.5M solution in cyclohexane) was added dropwise to the solution and the reaction mixture was stirred at the same temperature for 15 minutes. Carbon dioxide gas was bubbled in for 10 minutes and the temperature was allowed to rise to 0°C. The reaction mixture was poured into ice water (40ml) and washed twice with ether (40ml each). The aqueous layer was separated, adjusted to pH 4 with potassium dihydrogen phosphate, and extracted twice with ethyl acetate (40 ml each time). The combined extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to obtain the title compound (0.31 g, yield 90%) as a colorless oil.

IR spectrum (KBr) v _max cm ^-1 : 3474, 3358, 3326, 3194, 1683, 1673, 1611,

1538, 1503;

NMR spectrum (CDCl ₃ ) δppm: 1.38 (9H, s), 3.62 (2H, q, J=5.1Hz),

4.52(2H,t,J=5.1Hz), 5.27(1H,brs), 6.04(1H,brs), 6.40(1H,brs),

7.34 (1H, t, J=9.1Hz), 7.48 (1H, dd, J=9.1Hz, J=3.6Hz). (b) 3-(2-(N-tert-butoxycarbonylamino)ethoxy) -4-carbamoyl-5-fluoro-1,2-benzisoxazole

Under stirring at 5°C, 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-carboxy-5-fluoro-1,2-benzisoxazole (0.31g) in tetrahydrofuran ( 20 ml) solution were added tert-butyl chloroformate (0.14 g) and triethylamine (0.11 g), and the mixture was stirred for 15 minutes. Ammonia-saturated tetrahydrofuran solution (saturated at room temperature, 5 ml) was added to the reaction mixture and stirred for 15 minutes. The reaction mixture was poured into ice water (40ml), extracted with diethyl ether (twice, 40ml each), and the combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (4/1) as the eluent to obtain the title compound as a colorless powder (0.24 g, yield 78%) .

Melting point: 63-65°C;

IR spectrum (KBr) v _max cm ^-1 : 3473, 3359, 3327, 3195, 1683, 1673, 1612,

1538, 1503;

NMR spectrum (CDCl ₃ ) δppm: 1.38 (9H, s), 3.62 (2H, q, J=5.1Hz),

4.52(2H,t,J=5.1Hz), 5.27(1H,brs), 6.04(1H-brs), 6.40(1H,brs),

7.34 (1H, t, J=9.5Hz), 7.48 (1H, dd, J=9.5Hz, J=3.6Hz). (c) 3-(2-aminoethoxy)-4-carbamoyl-5 -Fluoro-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-carbamoyl-5-fluoro-1,2- Benzisoxazole (25mg) and 4N hydrochloric acid/dioxane solution (0.2ml) gave the title compound (20mg, 99%) as a colorless powder.

Melting point: 201-205°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3382, 3400-2400, 1656, 1605, 1590, 1543;

NMR spectrum (DMSO-d ₆ ) δppm: 3.30 (2H, t, J=5.1Hz), 4.62 (2H, t, J=5.1Hz),

7.63 (1H, t, J=9.5Hz), 7.77 (1H, dd, J=9.5Hz, J=3.6Hz), 7.86 (1H, brs),

8.19 (4H, brs). Example 19 3-(2-aminoethoxy)-4-cyano-5-fluoro-1,2-benzisoxazole hydrochloride (a) 3-(2-( N-tert-butoxycarbonylamino)ethoxy)-4-cyano-5-fluoro-1,2-benzisoxazole

Under stirring at 5°C, to 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-carbamoyl-5-fluoro-1,2-benzisoxazole (0.25g) To the solution of dimethylformamide (2.0ml) was added phosphorous oxychloride (0.12g), and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water (20 ml), extracted with ethyl acetate (twice, 20 ml each), and the combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (4/1) as the eluent to obtain the title compound as a colorless powder (0.20 g, yield 87%) .

Melting point: 116-117°C;

IR spectrum (KBr) v _max cm ^-1 : 3368, 2240, 1702, 1532, 1507;

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 3.67 (2H, q, J=5.1Hz),

4.54(2H, t, J=5.1Hz), 5.05(1H, brs), 7.43(1H, t, J=9.5Hz),

7.68 (1H, dd, J=9.5Hz, J=3.6Hz).(b) 3-(2-aminoethoxy)-4-cyano-5-fluoro-1,2-benzisoxazole salt salt

According to the similar reaction and treatment described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-cyano-5-fluoro-1,2-benzene Diisoxazole (0.17g) and 4N hydrochloric acid/dioxane solution (1.3ml) gave the title compound (0.12g, yield 96%) as a colorless powder.

Melting point: 190-193°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 2240, 1607, 1541, 1505;

NMR spectrum (DMSO-d ₆ ) δppm: 3.34 (2H, t, J=5.2Hz), 4.72 (2H, t, J=5.2Hz),

7.91 (1H, t, J=9.5Hz), 8.19 (1H, dd, J=9.5Hz, J=3.7Hz), 8.30 (3H, brs). Example 203-(2-aminoethoxy)-5 -Fluoro-4-methoxycarbonyl-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-fluoro-4-methanol Oxycarbonyl-1,2-Benzisoxazole

Add 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-carboxy-5-fluoro-1,2-benzisoxazole (0.31g) to ether (20ml) at 5°C To the solution was added diazomethane/ether solution until the reaction mixture turned yellow, then the mixture was stirred for 15 minutes. The reaction mixture was evaporated under reduced pressure to obtain the title compound (0.32 g, yield 100%) as an oil.

IR spectrum (KBr) v _max cm ^-1 : 3457, 1733, 1713, 1541, 1504;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.62 (2H, q, J=5.1Hz), 4.01 (3H, s),

4.49(2H, t, J=5.1Hz), 5.08(1H, brs), 7.35(1H, t, J=9.5Hz),

7.52 (1H, dd, J=9.5Hz, J=3.6H.z).(b) 3-(2-aminoethoxy)-5-fluoro-4-methoxycarbonyl-1,2-benzisoxazole The hydrochloride was reacted and treated similarly to that described in Example 17(c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-fluoro-4-methoxycarbonyl-1 , 2-Benzisoxazole (0.18g) and 4N-hydrochloric acid/dioxane solution (1.3ml) gave the title compound (0.15g, yield 97%) as a colorless powder.

Melting point: 168-170°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1729, 1584, 1539, 1501;

NMR spectrum (DMSO-d ₆ ) δppm: 3.31 (2H, t, J=5.1 Hz), 3.96 (3H, s),

4.62 (2H, t, J = 5.1Hz), 7.73 (2H, t, J = 9.5Hz), 7.96 (2H, dd, J = 9.5Hz, J = 3.6Hz),

8.23(3H, brs). Example 21 3-(2-aminoethoxy)-5-fluoro-4-methylthio-1,2-benzisoxazole hydrochloride (a)3-(2- (N-tert-butoxycarbonylamino)ethoxy)-5-fluoro-4-methylthio-1,2-benzisoxazole

3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-fluoro-1,2-benzisoxazole (0.30 g) in tetrahydrofuran ( 20ml) lithium diisopropylamide (1.50ml, 1.5M solution in cyclohexane) was added dropwise, and after stirring at the same temperature for 15 minutes, dimethyl disulfide (0.21g) was added. The reaction mixture was stirred at -70°C for 15 minutes, then the temperature was allowed to rise to 0°C. The reaction mixture was poured into ice water (40 ml), extracted with ethyl acetate (twice, 40 ml each), and the combined extracts were dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (9/1) as eluent to obtain the title compound (0.32 g, yield 94%).

Melting point: 91-92°C;

IR spectrum (KBr) v _max cm ^-1 : 3335, 1694, 1618, 1540;

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 2.60 (3H, d, J=2.1Hz),

3.67(2H, q, J=5.1Hz), 4.50(2H, t, J=5.1Hz), 5.04(1H, brs), 7.20-7.30(2H, m).(b) 3-(2-Aminoethyl Oxy)-5-fluoro-4-methylthio-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-fluoro-4-methylthio-1,2- Benzisoxazole (0.18g) and 4N hydrochloric acid/dioxane solution (1.3ml) gave the title compound (0.15g, yield 99%) as a colorless powder.

Melting point: 183-185°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3400-2400, 1617, 1592, 1535;

NMR spectrum (DMSO-d ₆ ) δppm: 2.57 (3H, d, J=1.4Hz), 3.35 (3H, t, J=5.1Hz),

4.64 (2H, t, = 5.1Hz), 7.59 (1H, t, J = 9.5Hz), 7.63 (1H, dd, J = 9.5Hz, J = 3.6Hz),

8.24(3H, brs). Example 22 3-(2-aminoethoxy)-4-methoxycarbonyl-1,2-benzisoxazole hydrochloride and 3-(2-aminoethoxy)- 7-Methoxycarbonyl-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole

To a solution of triphenylphosphine (0.95 g) in tetrahydrofuran (20 ml) was added diethyl azodicarboxylate (0.63 g) with stirring at 5°C, followed by stirring at the same temperature for 15 minutes. 3-Hydroxy-1,2-benzisoxazole (0.45 g) was added to the reaction mixture and stirred for 15 minutes, then N-t-butoxycarbonylethanolamine (0.53 g) was added and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (9/1) as eluent to obtain the title compound (0.63 g, 68%).

Melting point: 106-107°C;

IR spectrum (KBr) v _max cm ^-1 : 3326, 1716, 1707, 1615, 1536;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.65 (2H, q, J=5.1Hz),

4.51 (2H, t, J=5.1Hz), 4.90-5.05 (1H, brs), 7.26-7.66 (4H, m). (b) 3-(2-(N-tert-butoxycarbonylamino)ethoxy )-4-methoxycarbonyl-1,2-benzisoxazole and 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-methoxycarbonyl-1,2-benzisoxazole Oxazole

Into a solution of 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole (0.28g) in tetrahydrofuran (30ml) under a nitrogen atmosphere at -70°C with stirring Butyllithium (1.40 ml, 1.6M hexane solution) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. Carbon dioxide gas was bubbled through the reaction mixture for 10 minutes and the temperature was allowed to rise to 0°C. The reaction mixture was poured into ice water (40ml) and extracted with ether (twice, 40ml each). The aqueous layer was separated, adjusted to pH 4 with potassium dihydrogen phosphate, and extracted with ethyl acetate (twice, 40 ml each). The combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-methoxycarbonyl-1,2-benzisoxazole and 3-(2-(N- tert-butoxycarbonylamino)ethoxy)-7-methoxycarbonyl-1,2-benzisoxazole colorless oily mixture (0.31 g, 92%).

The resulting mixture was dissolved in diethyl ether (15ml), then cooled to 5°C, diazomethane/diethyl ether solution was added dropwise until the reaction mixture turned yellow, and then the mixture was stirred at the same temperature for 15 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (4/1) as eluent to obtain the title compound 3-(2-(N- tert-butoxycarbonylamino)ethoxy)-4-methoxycarbonyl-1,2-benzisoxazole (0.15g, 45%) and 3-(2-(N-tert-butoxycarbonylamino)ethoxy yl)-7-methoxycarbonyl-1,2-benzisoxazole (0.08 g, 24%).

Data on 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-methoxycarbonyl-1,2-benzisoxazole.

Melting point: 95-96°C;

IR spectrum (KBr) v _max cm ^-1 : 3397, 1705, 1601, 1533, 1524, 1503;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.66 (2H, q, J=5.1Hz), 3.99 (3H, s),

4.51(2H, t, J=5.1Hz), 529(1H, brs), 7.55-7.65(2H, m), 7.85(1H, d, J=7.5Hz).

Data on 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-methoxycarbonyl-1,2-benzisoxazole.

Melting point: 90-91°C;

IR spectrum (KBr) v _max cm ^-1 : 3387, 1718, 1693, 1620, 1610, 1552, 1525;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.66 (2H, q, J=5.1Hz), 4.03 (3H, s),

4.54 (2H, t, J = 5.1Hz), 4.96 (1H, brs), 7.37 (1H, t, J = 8.1Hz), 7.85 (1H, d, J = 8.1Hz),

8.23 (3H, d, J=8.0Hz). (c) 3-(2-aminoethoxy)-4-methoxycarbonyl-1,2-benzisoxazole hydrochloride

According to the reaction and treatment similar to that described in Example 17(c), 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-methoxycarbonyl-1,2-benzoisoxane Azole (0.10 g) and 4N hydrochloric acid/dioxane solution (1.0 ml) gave the title compound (0.08 g, yield 100%) as a colorless powder.

Melting point: 169-172°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1718, 1601, 1525, 1499;

NMR spectrum (DMSO-d ₆ ) δppm: 3.34 (2H, t, J=5.1Hz), 3.93 (3H, s),

4.62(2H, t, J=5.1Hz), 7.75-7.85(2H, m), 7.95(1H, d, J=8.1Hz), 8.23(3H, brs).(d) 3-(2-aminoethyl Oxy)-7-methoxycarbonyl-1,2-benzisoxazole hydrochloride

According to the reaction and treatment similar to that described in Example 17(c), 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-methoxycarbonyl-1,2-benzoisoxane Azole (0.08g) and 4N-hydrochloric acid/dioxane solution (1.0ml) gave the title compound (0.06g, yield 100%) as a colorless powder.

Melting point: 211-213°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1730, 1719, 1618, 1608, 1550, 1502;

NMR spectrum (DMSO-d ₆ ) δppm: 3.36 (2H, t, J=5.1Hz), 3.95 (3H, s),

4.65 (2H, t, J = 5.1Hz), 7.56 (1H, t, J = 8.0Hz), 8.10 (1H, d, J = 8.1Hz),

8.23 (1H, d, J=8.1Hz), 8.30 (3H, brs). Example 23 3-(2-aminoethoxy)-4-carbamoyl-1,2-benzisoxazole hydrochloride and 3-(2-aminoethoxy)-7-carbamoyl-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy )-4-carbamoyl-1,2-benzisoxazole and 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-carbamoyl-1,2-benzisoxazole Oxazole

Into a solution of 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole (0.55g) in tetrahydrofuran (30ml) under a nitrogen atmosphere at -70°C with stirring Butyllithium (3.0 ml, 1.6M hexane solution) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. Carbon dioxide gas was bubbled through the reaction mixture for 10 minutes and the temperature was allowed to rise to 0°C. The reaction mixture was poured into ice water (40ml) and extracted with ether (twice, 40ml each). The aqueous layer was separated, adjusted to pH 4 with potassium dihydrogen phosphate, and extracted with ethyl acetate (twice, 40 ml each). The combined extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to give 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-carboxy-1,2-benziso Colorless oily mixture of oxazole and 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-carboxy-1,2-benzisoxazole (0.48 g).

Then, the resulting mixture was dissolved in tetrahydrofuran (30 ml), and to this solution were added isobutyl chloroformate (0.23 g) and triethylamine (0.18 g) under stirring at 5° C., and the mixture was stirred for 15 minutes, followed by Ammonia-saturated tetrahydrofuran solution (saturated at room temperature, 5 mL) was added and stirred for 15 minutes. The reaction mixture was poured into ice water (40 ml), extracted with ethyl acetate (twice, 40 ml each), and the combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (4/1) as eluent to obtain 3-(2-(N-tert-butoxycarbonyl) as colorless powder Amino)ethoxy)-4-carbamoyl-1,2-benzisoxazole (0.30g, 47%) and 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7 -Carbamoyl-1,2-benzisoxazole (0.17 g, 26%).

Data on 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-carbamoyl-1,2-benzisoxazole.

Melting point: 119-120°C;

IR spectrum (KBr) v _max cm ^-1 : 3488, 3443, 3358, 3196, 1688, 1663, 1610,

1592, 1533;

NMR spectrum (CDCl ₃ ) δppm: 1.42 (9H, s), 3.70 (2H, q, J=5.1Hz),

4.62(2H, t, J=5.1Hz), 4.93(1H, brs), 5.91(1H, brs), 7.60-7.70(2H, m),

7.79(1H, brs), 8.14(1H, d, J=7.0Hz)

Data on 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-carbamoyl-1,2-benzisoxazole.

Melting point: 151-153°C;

IR spectrum (KBr) v _max cm ^-1 : 3463, 3396, 3353, 3304, 3232, 3182, 1716,

1680, 1618, 1544;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.67 (2H, q, J=5.1Hz),

4.54(2H,t,J=5.1Hz), 4.97(1H,brs), 5.95(1H,brs), 7.14(1H,brs),

7.44 (1H, t, J = 7.0Hz), 7.83 (1H, d, J = 7.0Hz), 8.35 (1H, d, J = 7.0Hz). (b) 3-(2-Aminoethoxy)- 4-carbamoyl-1,2-benzisoxazole hydrochloride

According to the reaction and treatment similar to that described in Example 17(c), 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-carbamoyl-1,2-benzoisoxane Azole (0.10 g) and 4N-hydrochloric acid/dioxane solution (1.0 ml) gave the title compound (0.08 g, yield 100%) as a colorless powder.

Melting point: 210-213°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3383, 3300-2400, 1656, 1605, 1590, 1543;

NMR spectrum (DMSO-d ₆ ) δppm: 3.57 (2H, t, J=5.1Hz), 4.64 (2H, t, J=5.1Hz),

7.58 (1H, d, J = 7.0Hz), 7.71 (1H, brs), 7.73 (1H, dd, J = 9.0Hz, J = 7.0Hz),

7.79 (1H.d, J=9.0Hz), 7.99 (1H, brs), 8.21 (3H, brs). (c) 3-(2-aminoethoxy)-7-carbamoyl-1,2- Benzisoxazole Hydrochloride

According to the reaction and treatment similar to that described in Example 17(c), 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-carbamoyl-1,2-benzoisoxane Azole (0.05g) and 4N-hydrochloric acid/dioxane solution (1.0ml) gave the title compound (0.04g, yield 100%) as a colorless powder.

Melting point: 227-230°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3461, 3180, 3300-2400, 1675, 1618, 1596,

1547;

NMR spectrum (DMSO-d ₆ ) δppm: 3.34 (2H, t, J=5.1Hz), 4.65 (2H, t, J=5.1Hz),

7.50(1H, t, J=7.0Hz), 7.77(1H, brs), 7.83(1H, brs), 7.95(1H, d, J=7.0Hz),

8.05 (1H, d, J=7.0Hz), 8.31 (3H, brs) Example 24 3-(2-aminoethoxy)-4-cyano-1,2-benzisoxazole hydrochloride (a )3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-cyano-1,2-benzisoxazole

Under stirring at 5°C, 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-carbamoyl-1,2-benzisoxazole (0.15 g) To the solution of amide (1.5ml) was added phosphorus oxychloride (0.9g), and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water (20 ml), extracted with ethyl acetate (twice, 20 ml each), and the combined extracts were dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (4/1) as eluent to obtain the title compound (0.13 g, 93% ).

Melting point: 116-117°C;

IR spectrum (KBr) v _max cm ^-1 : 3370, 2232, 1701, 1601, 1530;

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 3.69 (2H, q, J=5.1Hz),

4.55 (2H, t, J=5.1Hz), 5.08 (1H, brs), 7.60-7.75 (3H, m) (b) 3-(2-aminoethoxy)-4-cyano-1,2- Benzisoxazole Hydrochloride

Reaction and treatment according to the similar method described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-cyano-1,2-benzisoxazole (0.10 g) and 4N = hydrochloric acid/dioxane solution (1.0 ml) to obtain the title compound (0.08 g, yield 100%) as a colorless powder.

Melting point: 210-213°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3400-2400, 2234, 1601, 1538;

NMR spectrum (DMSO-d ₆ ) δppm: 3.35 (2H, t, J=5.1Hz), 4.72 (2H, t, J=5.1Hz),

7.87 (1H, t, J = 8.1Hz), 7.98 (1H, d, J = 8.1Hz), 8.09 (1H, d, J = 8.1Hz), 8.26 (3H, brs). Example 253-(2- Aminoethoxy)-7-cyano-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-cyano- 1,2-Benzisoxazole

Under stirring at 5°C, 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-carbamoyl-1,2-benzisoxazole (0.10g) in dimethyl form To the amide (1.0 ml) solution was added phosphorous oxychloride (0.06 g), and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water (20 ml), extracted with ethyl acetate (twice, 20 ml each), and the combined extracts were dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (4/1) as eluent to obtain the title compound (0.09 g, 90% ).

Melting point: 91-92°C;

IR spectrum (KBr) v _max cm ^-1 : 3437, 3349, 3316, 2238, 1719, 1701, 1688,

1621, 1607, 1546, 1528;

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 3.66 (2H, q, J=5.1Hz),

4.54 (2H, t, J = 5.1Hz), 4.92 (1H, brs), 7.40 (1H, t, J = 8.0Hz), 7.86 (1H, d, J = 8.0Hz),

7.90 (1H, d, J=8.0Hz). (b) 3-(2-aminoethoxy)-7-cyano-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-cyano-1,2-benzisoxazole (0.07g) and 4N-hydrochloric acid/dioxane (1.0ml) to obtain the title compound (0.05g, yield 100%) as a colorless powder.

Melting point: 205-208°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3241, 3400-2400, 2239, 1623, 1607, 1547;

NMR spectrum (DMSO-d ₆ ) δppm: 3.36 (2H, t, J=5.1Hz), 4.67 (2H, t, J=5.1Hz),

7.61 (1H, t, J = 8.1Hz), 8.18 (1H, d, J = 8.1Hz), 8.26 (1H, d, J = 8.1Hz), 8.34 (3H, brs). Example 263-(2- Aminoethylthio)-5-fluoro-1,2-benzisoxazole hydrochloride (a) 3-chloro-5-fluoro-1,2-benzisoxazole

To a solution of 5-fluoro-3-hydroxyisoxazole (1.0 g) in pyridine (0.53 ml) was added phosphorus oxychloride (0.89 g) and the mixture was refluxed for 8 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, and the combined extracts were washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.85 g, 77%) as a colorless oil. (b) 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-fluoro-1,2-benzisoxazole

Under a nitrogen atmosphere, 2-tert-butoxycarbonylaminoethanethiol ( 0.86 g) and potassium carbonate (0.67 g), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, and the combined extracts were washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.21 g, 80%) as a colorless powder.

NMR spectrum (CDCl ₃ ) δppm: 1.44 (9H, s), 3.41 (2H, t, J=6.2Hz),

3.58 (2H, td, J=6.2Hz, J=6.2Hz), 4.98 (1H, brs), 7.21-7.51 (3H, m). (c) 3-(2-Aminoethylthio)-5-fluoro-1,2-benzisoxazole hydrochloride

Under stirring at 5°C, 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-fluoro-1,2-benzisoxazole (0.20g) in dioxane (2ml) To the solution was added 4N-hydrochloric acid/dioxane solution (0.8 ml), and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol and ethyl acetate to obtain the title compound (0.14 g) as colorless needles.

Melting point: 202-206°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 2992, 2955, 2915, 1594, 1511, 1493;

NMR spectrum (DMSO-d ₆ ) δppm: 3.25 (2H, t, J = 7.1 Hz), 3.53 (2H, t, J = 7.1 Hz),

7.60-7.86 (3H, m), 8.22 (3H, brs). Example 27 3-(2-aminoethylthio)-7-chloro-1,2-benzisoxazole hydrochloride (a) 3,7-dichloro-1,2-benzisoxazole

The title compound (0.73 g, 78% ). (b) 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-7-chloro-1,2-benzisoxazole

The title compound (0.22 g, 63%) was obtained from 3,7-dichloro-1,2-benzisoxazole (0.20 g) by reaction and treatment in a manner similar to that described in Example 26(b). .

NMR spectrum (CDCl ₃ ) δppm: 1.43 (9Hs,), 3.42 (2H, t, J=6.2Hz),

3.60(2H,td,J=6.2HzJ=6.2Hz), 5.01(1H,brs), 7.24(1H,t,J=9.1Hz),

7.48 (1H, d, J=9.1Hz), 7.56 (1H, d, J=9.1Hz). (c) 3-(2-aminoethylthio)-7-chloro-1,2-benzoisoxane azole hydrochloride

According to the similar reaction and treatment described in Example 26 (c), 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-7-chloro-1,2-benzisoxazole ( 0.15 g) yielded the title compound (0.12 g, quantitative).

Melting point: 196-201°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 2971, 2909, 1592, 1502, 1492;

NMR spectrum (DMSO-d ₆ ) δppm: 3.26 (2H, t, J=7.1Hz), 3.56 (2H, t, J=7.1Hz),

7 45 (1H, t, J=7.9Hz), 7.79 (1H, d, J=7.9Hz), 7.86 (1H, d, J=7.9Hz), 8.20 (3H, brs). Embodiment 283-(2 -Aminoethylthio)-7-methyl-1,2-benzisoxazole hydrochloride (a) 3-chloro-7-methyl-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 26 (a), the title compound (0.30 g, 77 %). (b) 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-7-methyl-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 26 (b), the title compound (0.24 g, 55 %).

NMR spectrum (CDCl ₃ ) δppm: 1.43 (9H, s), 2.52 (3H, s), 3.42 (2H, t, J=6.2Hz), 3.58 (2H, rd, J=6.2Hz, J=6.2Hz) , 5.12(1H, brs), 7.18(1H, t, J=9.1Hz), 7.33(1H, d, J=9.1Hz), 7.40(1H, d, J=9.1Hz).(c)3-( 2-aminoethylthio)-7-methyl-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 26 (c), from 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-7-methyl-1,2-benzisoxazole (0.10 g) yielded the title compound (0.08 g, quantitative).

Melting point: 198-203°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 2985, 2913, 1598, 1501;

NMR spectrum (DMSO-d ₆ ) δppm: 2.51 (3H, s), 3.24 (2H, t, J=7.1Hz),

3.54 (2H, t, J = 7.1Hz), 7.33 (1H, t, J = 7.4Hz), 7.52 (1H, d, J = 7.4Hz),

7.58 (1H, d, J=7.4Hz), 8.22 (3H, brs). Example 29 3-(2-aminoethylthio)-5,7-dichloro-1,2-benzisoxazole hydrochloride Salt (a) 3,5,7-trichloro-1,2-benzisoxazole

The title compound (1.81g , 83%). (b) 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5,7-dichloro-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 26 (b), the title compound (0.25 g, 68 %).

NMR spectrum (CDCl ₃ ) δppm: 1.43 (9H, s), 3.42 (2H, t, J=6.2Hz),

3.58(2H, td, J=6.2Hz, J=6.2Hz), 5.03(1H, brs), 7.48(1H, s), 7.56(1H, s).(c) 3-(2-Aminoethylthio )-5,7-dichloro-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 26 (c), from 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5,7-dichloro-1,2-benziso Oxazole (0.22 g) gave the title compound (0.18 g, quantitative).

Melting point: 199-202°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3003, 2970, 2915, 1590, 1480;

NMR spectrum (DMSO-d ₆ ) δppm: 3.25 (1H, t, J=6.9Hz), 3.54 (2H, t, J=6.9Hz),

8.00 (1H, s), 8.06 (1H, s), 8.18 (3H, brs). Example 30 3-(2-aminoethylthio)-7-nitro-1,2-benzisoxazole hydrochloride (a) 3-chloro-7-nitro-1,2-benzisoxazole azole

According to the reaction and treatment similar to that described in Example 26 (a), the title compound (0.93 g, 80 %). (b) 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-7-nitro-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 26 (b), the title compound (0.20 g, 51 %).

NMR spectrum (CDCl ₃ ) δppm: 1.43 (9H, s), 3.48 (2H, t, J=6.2Hz),

3.62(2H, td, J=6.2Hz, J=6.2Hz), 4.98(1H, brs), 7.50(1H, t, J=9.1Hz),

7.94 (1H, d, J=9.1Hz), 8.44 (1H, d, J=9.1Hz). (c) 3-(2-aminoethylthio)-7-nitro-1,2-benziso Oxazole hydrochloride

Reaction and treatment according to the similar method described in Example 26 (c), from 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-7-nitro-1,2-benzisoxazole (0.18 g) yielded the title compound (0.14 g, quantitative).

Melting point: 193-196°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 2990, 2924, 2882, 1620, 1589, 1532, 1512;

NMR spectrum (DMSO-d ₆ ) δppm: 3.28 (2H, t, J=7.1Hz), 3.61 (2H, t, J=7.1Hz),

7.69 (1H, t, J = 7.9Hz), 8.24 (3H, brs), 8.29 (1H, d, J = 7.9Hz), 8.57 (1H, d, J = 7.9Hz). Example 313-(2- Aminoethylthio)-7-methoxy-1,2-benzisoxazole hydrochloride (a) 3-chloro-7-methoxy-1,2-benzisoxazole

The title compound (0.61 g, 69%). (b) 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-7-methoxy-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 26(b), the title compound (0.25 g, 54%).

NMR spectrum (CDCl ₃ ) δppm: 1.44 (9H, s), 3.42 (2H, t, J=6.2Hz),

3.58(2H, td, J=6.2Hz, J=6.2Hz), 4.04(3H, s), 5.02(1H, brs), 6.98(1H, d, J=9.1Hz),

7.15 (1H, d, J=9.1Hz), 7.23 (1H, t, J=9.1Hz). (c) 3-(2-aminoethylthio)-7-methoxy-1,2-benzo Isoxazole hydrochloride

According to the reaction and treatment similar to that described in Example 26(c), 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-7-methoxy-1,2-benzoisoxane Azole (120 mg) was used to obtain the title compound (90 mg, quantitative).

Melting point: 232-237°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3019, 2969, 2907, 1619, 1600, 1512;

NMR spectrum (DMSO-d ₆ ) δppm: 3.25 (2H, t, J = 7.1 Hz), 3.54 (2H, t, J = 7.1 Hz),

3.98 (3H, s), 7.27-7.40 (3H, m), 8.21 (3H, brs). Example 32 3-(2-aminoethylthio)-7-amino-1,2-benzisoxazole dihydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethylthio )-7-amino-1,2-benzisoxazole

Under ice-cooling and stirring, 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-7-nitro-1,2-benzisoxazole (250 mg) in 90% acetic acid aqueous solution ( 2 ml) was added zinc powder (250 mg), and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using ethyl acetate as eluent to obtain the title compound (230 mg, quantitative).

NMR spectrum (CDCl ₃ ) δppm: 1.43 (9H, s), 3.4 1 (2H, t, J=6.2Hz),

3.59(2H, td, J=6.2Hz, J=6.2Hz), 4.08(2H, brs), 5.02(1H, brs),

6.82 (1H, d, J = 8.7Hz), 6.96 (1H, d, J = 8.7Hz), 7.12 (1H, t, J = 8.7Hz). (b) 3-(2-Aminoethylthio)- 7-amino-1,2-benzisoxazole dihydrochloride

According to the similar method reaction and treatment described in Example 26 (c), 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-7-amino-1,2-benzisoxazole ( 140 mg) to obtain the title compound (120 mg, quantitative).

Melting point: 157-160°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 :, 3035, 2969, 2884, 2807, 2581, 1631, 1614,

1570, 1521, 1504;

NMR spectrum (DMSO-d ₆ ) δppm: 3.24 (2H, t, J=7.0Hz), 3.52 (2H, t, J=7.0Hz),

4.05-5.35 (2H, brs), 6.88 (2H, d, J=7.9Hz), 7.12 (1H, t, J=7.9Hz), 8.23 (3H, brs). Example 333-(2-Aminoethylsulfur Base)-5-methoxy-1,2-benzisoxazole hydrochloride (a) 3-chloro-5-methoxy-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 26 (a), the title compound (730 mg, 71% ). (b) 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-methoxy-1,2-benzisoxazole

The title compound (280 mg, 61% ).

MR spectrum (CDCl ₃ ) δppm: 1.43 (9H, s), 3.40 (2H, t, J=6.2Hz),

3.58(2H, td, J=6.2Hz, J=6.2Hz), 3.86(3H, s), 5.02(1H, brs), 6.91(1H, s),

7.18 (1H, d, J = 91 Hz), 7.43 (1 H, d, J = 9.1 Hz). (c) 3-(2-Aminoethylthio-5-methoxy-1,2-benzisoxazole hydrochloride

According to the reaction and treatment similar to that described in Example 26(c), 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-methoxy-1,2-benzoisoxane Azole (240 mg) gave the title compound (190 mg, quantitative).

Melting point: 213-217°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 2997, 2947, 2883, 1592, 1514, 1495;

NMR spectrum (DMSO-d ₆ ) δppm: 3.23 (2H, t, J=7.1Hz), 3.52 (2H, t, J=7.1Hz),

3.84(3H, s), 7.16(1H, s), 7.32(1H.d, J=9.1Hz), 7.69(1H,d, J=9.1Hz),

8.17 (3H, brs). Example 34 3-(2-aminoethylthio)-5-methyl-1,2-benzisoxazole hydrochloride (a) 3-chloro-5-methyl-1 , 2-Benzisoxazole

According to the reaction and treatment similar to that described in Example 26 (a), the title compound (0.81 g, 71 %). (b) 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-methyl-1,2-benzisoxazole

The title compound (90 mg, 56%) was obtained from 3-chloro-5-methyl-1,2-benzisoxazole (90 mg) by reaction and treatment in a similar manner as described in Example 26(b). .

NMR spectrum (CDCl ₃ ) δppm: 1.44 (9H, s), 2.46 (3H, s), 3.40 (2H, t, J=6.2Hz),

3.58(2H, td, J=6.2Hz, J=6.2Hz), 5.02(1H, brs), 7.38(2H, d, J=9.1Hz), 7.42(1H, s).(c)3-(2 -Aminoethylthio)-5-methyl-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 26 (c), from 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5-methyl-1,2-benzisoxazole (80 mg) yielded the title compound (60 mg, quantitative).

Melting point: 132-135°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 2996, 2919, 1600, 1592, 1497;

NMR spectrum (DMSO-d ₆ ) δppm: 2.44 (3H, s), 3.24 (2H, t, J=7.1Hz),

3.53(2H,t,J=7.1Hz), 7.54(1H.d.J=8.5Hz), 7.55(1H,s), 7.65(1H,d,J=8.5Hz),

8.21 (3H, brs) Example 35 3-(2-aminoethylthio)-5-nitro-1,2-benzisoxazole hydrochloride (a) 3-chloro-5-nitro-1, 2-Benzisoxazole

According to the similar reaction and treatment described in Example 26 (a), the title compound (0.63 g, 56 %). (b) 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-nitro-1,2-benzisoxazole

The title compound (560 mg, 58%) was obtained from 3-chloro-5-nitro-1,2-benzisoxazole (560 mg) according to the reaction and treatment similar to that described in Example 26(b). .

NMR spectrum (CDCl ₃ ) δppm: 1.44 (9H, s), 3.47 (2H, t, J=6.2Hz),

3.62(2H, td, J=6.2Hz, J=6.2Hz), 4.96(1H, brs), 7.64(1H, d, J=9.1Hz),

8.48(1H, d, J=9.1Hz), 8.56(1H, s).(c) 3-(2-aminoethylthio)-5-nitro-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 26 (c), from 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5-nitro-1,2-benzisoxazole (250 mg) yielded the title compound (200 mg, quantitative).

Melting point: 183-186°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3031, 2971, 2892, 1619, 1594, 1530;

NMR spectrum (DMSO-d ₆ ) δppm: 3.26 (2H, t, J=7.1Hz), 3.59 (2H, t, J=7.1Hz),

8.03(1H, d, J=9.1Hz), 8.24(3H, brs), 8.56(1H, d, J=9.1Hz), 8.72(1H, s). Example 363-(2-Aminoethylthio) -5-amino-1,2-benzoisoxazole dihydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-amino-1,2-benzo Isoxazole

According to the reaction and treatment similar to that described in Example 32 (a), from 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-nitro-1,2-benzisoxazole (150 mg) yielded the title compound (140 mg, quantitative).

NMR spectrum (CDCl ₃ ) δppm: 1.43 (3H, s), 3.37 (2H, t, J=6.1Hz),

3.57(2H, td, J=6.2Hz, J=6.2Hz), 3.91(2H, brs), 5.03(1H, brs), 6.77(1H, s),

6.94 (1H, d, J=8.7Hz), 7.33 (1H, d, J=8.7Hz). (b) 3-(2-aminoethylthio)-5-amino-1,2-benzoisoxane azole dihydrochloride

According to the similar method reaction and treatment described in Example 26 (c), from 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5-amino-1,2-benzisoxazole ( 200 mg) to obtain the title compound (200 mg, quantitative).

Melting point: 201-205°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3045, 3021, 2946, 2885, 1628, 1582, 1494;

NMR spectrum (DMSO-d ₆ ) δppm: 3.26 (2H, t, J=7.0Hz), 3.35-4.85 (2H, brs),

3.55(2H, t, J=7.0Hz), 7.54(1H, d, J=6.5Hz), 7.56(1H, s), 7.80(1H, d, J=6.5Hz),

8.24(3H, brs). Example 37 3-(2-aminoethoxy)-1,2-naphtho[2,3-e]isoxazole hydrochloride (a) 3-hydroxyl-1,2- Naphtho[2,3-e]isoxazole

The title compound (3.1 g, 31 %).

IR spectrum (KBr) v _max cm ^-1 : 3044, 3001, 2940, 2869, 2824, 2746, 2696,

2661, 2623, 1770, 1645, 1618, 1598, 1573, 1521;

NMR spectrum (DMSO-d ₆ ) δppm: 7.45-7.65 (2H, m), 8.01 (1H, s),

8.04 (1H, d, J = 8.4Hz), 8.15 (1H, d, J = 8.4Hz), 8.43 (1H, s), 12.67 (1H, brs). (b) 3-(2-(N-t Butoxycarbonylamino)ethoxy)-1,2-naphtho[2,3-e]isoxazole

According to the similar reaction and treatment described in Example 1 (e), 3-hydroxyl-1,2-naphtho[2,3-e]isoxazole (0.46g) and 2-(N-tert-butoxy Carbonylamino)ethanol to obtain the title compound (0.59 g, 72%).

Melting point: 148-149°C;

IR spectrum (KBr) v _max cm ^-1 : 3314, 1707, 1643, 1545, 1535;

NMR spectrum (CDCl ₃ ) δppm: 1.47 (9H, s), 3.70 (2H, q, J=5.1Hz),

4.59(2H, t, J=5.1Hz), 5.01(1H, brs), 7.33-7.60(2H, m), 7.81(1H, s),

7.94 (1H, d, J = 8.4Hz), 8.00 (1H, d, J = 8.4Hz), 8.22 (1H, s). (c) 3-(2-aminoethoxy)-1,2-naphthalene And[2,3-e]isoxazole hydrochloride

According to the similar reaction and treatment described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-1,2-naphtho[2,3-e]iso Oxazole (0.50 g) gave the title compound (0.40 g 99%).

Melting point: 207-213°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1641, 1615, 1545, 1516, 1505;

NMR spectrum (DMSO-d ₆ ) δppm: 3.39 (2H, q, J=5.1Hz), 4.71 (2H, t, J=5.1Hz),

7.50-7.70 (2H, m), 8.09 (1H, d, J = 8.4Hz), 8.13 (1H, s), 8.18 (1H, d, J = 8.4Hz),

8.36 (3H, brs), 8.47 (1H, s). Example 38 3-(2-aminoethylthio)-5-chloro-1,2-benzisoxazole hydrochloride (a)3-(2 -(N-tert-butoxycarbonylamino)ethylthio)-5-chloro-1,2-benzisoxazole

The title compound (0.63 g, 62%) was obtained from 3,5-dichloro-1,2-benzisoxazole (0.53 g) by reaction and treatment similar to that described in Example 26(b). .

Melting point: 95-96°C;

IR spectrum (KBr) v _max cm ^-1 : 3283, 1687, 1523;

NMR spectrum (CDCl ₃ ) δppm: 1.44 (9H, s), 3.42 (2H, t, J=6.3Hz),

3.58(2H, q, J=6.3Hz), 4.98(1H, brs), 7.47(1H, d, J=8.8Hz),

7.52 (1H, dd, J=8.8Hz, J=1.5Hz), 7.57 (1H, d, J=1.5Hz). (b) 3-(2-aminoethylthio)-5-chloro-1,2 -Benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 22 (c), 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5-chloro-1,2-benzisoxazole ( 0.52 g) yielded the title compound (0.41 g, 97%).

Melting point: 201-206°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1588, 1524;

NMR spectrum (DMSO-d ₆ ) δppm: 3.24 (2H, q, J=7.0Hz), 3.55 (2H, t, J=7.0Hz),

7.75 (1H, dd, J=8.9Hz, J=2.0Hz), 7.83 (1H, d, J=8.9Hz), 7.95 (1H, d, J=2.0Hz),

8.23(3H, brs). Example 39 3-(2-aminoethylthio)-5-fluoro-4-methyl-1,2-benzisoxazole hydrochloride (a) 3-(2-( N-tert-butoxycarbonylamino)ethylthio)-5-fluoro-4-methyl-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 17 (b), 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5-fluoro-1,2-benzisoxazole ( 0.11 g) yielded the title compound (0.10 g, 91%).

NMR spectrum (CDCl ₃ ) δppm: 1.44 (9H, s), 2.55 (3H, s), 3.42 (2H, t, J=6.1Hz),

3.58(2H, td, J=6.1Hz, J=6.1Hz), 5.02(1H, brs), 7.19-7.34(2H,m).(b) 3-(2-aminoethylthio)-5-fluoro -4-Methyl-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5-fluoro-4-methyl-1,2-benzene Isoxazole (0.09 g) gave the title compound (0.07 g, quantitative).

Melting point: 209-212°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3103, 2963, 2901, 1499;

NMR spectrum (DMSO-d ₆ ) δppm: 2.53 (3H, s), 3.26 (2H, t, J=6.9Hz),

3.55 (2H, t, J=6.9Hz), 7.53-7.65 (2H, m), 8.20 (3H, brs). Example 40 3-(2-aminoethylthio)-5-fluoro-4-cyano-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino ) ethylthio-5-fluoro-4-carbamoyl-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 18 (a), 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5-fluoro-1,2-benzisoxazole ( 0.30 g) yielded 3-(2-(N-tert-butoxycarbonylamino)ethylthio-5-fluoro-4-carboxy-1,2-benzisoxazole (0.25 g, 74%). Then, According to the similar reaction and treatment described in Example 18 (b), from 3-(2-(N-tert-butoxycarbonylamino)ethylthio-5-fluoro-4-carboxy-1,2-benziso Oxazole (0.23 g) gave the title compound (0.16 g, 70%).

NMR spectrum (CDCl ₃ ) δppm: 1.43 (9H, s), 3.35 (2H, t, J=6.1Hz),

3.58(2H, td, J=6.1Hz, J=6.1Hz), 5.03(1H, brs), 6.02(1H, brs), 6.29(1H, brs),

7.37 (1H, t, J=8.9Hz), 7.62 (1H, dd, J=3.8Hz, J=8.9Hz).(b) 3-(2-(N-tert-butoxycarbonylamino)ethylthio- 5-fluoro-4-cyano-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 19 (a), 3-(2-(N-tert-butoxycarbonylamino)ethylthio-5-fluoro-4-carbamoyl-1,2-benzene Isoxazole (0.14g) gave the title compound (0.12g, 92%).

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 3.46 (2H, t, J=6.0Hz),

3.60(2H, td, J=6.0Hz, J=6.0Hz), 4.97(1H, brs), 7.45(1H, t, J=8.9Hz),

7.77 (1H, dd, J=3.9Hz, J=8.9Hz).(c) 3-(2-Aminoethylthio)-5-fluoro-4-cyano-1,2-benzisoxazole salt salt

Reaction and treatment according to the similar method described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5-fluoro-4-cyano-1,2-benzene Isoxazole (0.11 g) gave the title compound (0.09 g, quantitative).

Melting point: 215-219°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3436, 3090, 3005, 1494;

NMR spectrum (DMSO-d ₆ ) δppm: 3.27 (2H, t, J=6.9Hz), 3.59 (2H, t, J=6.9Hz),

7.94 (1H, t, J=9 4Hz), 8.19 (3H, brs), 8.30 (1H, dd, J=3.9Hz, J=9.4Hz). Embodiment 413-(2-aminoethoxy)-7 -Methoxy-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-methoxy-1,2-benzene Isoxazole

According to the similar reaction and treatment described in Example 1 (e), the title compound (0.39 g, 63%).

Melting point: 98-99°C;

IR spectrum (KBr) v _max cm ^-1 : 3348, 1708, 1683, 1624, 1615, 1542, 1533,

1509;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.64 (2H, q, J=5.1Hz), 4.03 (3H, s),

4.51 (2H, t, J=5.1Hz), 4.97 (1H, brs), 6.95-7.00 (1H, m), 7.15-7.20 (2H, m). (b) 3-(2-aminoethoxy) -7-Methoxy-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-methoxy-1,2-benzoisoxane Azole (0.30 g) gave the title compound (0.23 g, 96%).

Melting point: 208-213°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3022, 2983, 2909, 2840, 1627, 1614, 1546,

1509;

NMR spectrum (DMSO-d ₆ ) δppm: 3.30 (2H, t, J=5.1Hz), 3.97 (3H, s),

4.61 (2H, t, J=5.1Hz), 7.20-7.25 (1H, m), 7.30-7.35 (2H, m), 8.29 (3H, brs). Example 423-(2-Aminoethoxy)- 5-Methoxycarbonyl-1,2-benzisoxazole hydrochloride (a) 5-bromo-3-(2-(N-tert-butoxycarbonylamino)ethoxy)-1,2-benzo Isoxazole

According to the similar reaction and treatment described in Example 1 (e), from 5-bromo-3-hydroxyl-1,2-benzisoxazole (4.30g) and 2-(N-tert-butoxycarbonylamino) Ethanol yielded the title compound (4.80 g, 67%).

Melting point: 123-124°C;

IR spectrum (KBr) v _max cm ^-1 : 3313, 1699, 1683, 1611, 1545;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (3H, s), 3.64 (2H, q, J=5.1Hz),

4.50 (2H, t, J = 5.1Hz), 4.92 (1H, brs), 7.33 (1H, d, J = 8.9Hz),

7.62 (1H, dd. J = 8.9Hz, J = 1.9Hz), 7.80 (1H, d, J = 1.9Hz). (b) 3-(2-(N-tert-butoxycarbonylamino)ethoxy) -5-methoxycarbonyl-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 22 (b), 5-bromo-3-(2-(N-tert-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole ( 1.00 g) yielded the title compound (0.27 g, 29%).

Melting point: 154-155°C;

IR spectrum (KBr) v _max cm ^-1 : 3326, 1720, 1702, 1687, 1629, 1611, 15477;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.66 (2H, q, J=5.1Hz),

3.96(3H, s), 4.53(2H, t, J=5.1Hz), 4.97(1H, brs), 7.47(1H, d, J=8.8Hz),

8.24 (1H, dd, J=8.8Hz, J=1.6Hz), 8.41 (1H,d, J=1.6Hz). (c) 3-(2-aminoethoxy)-5-methoxycarbonyl-1,2-benzisoxazole hydrochloride

According to the reaction and treatment similar to that described in Example 22(c), 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-methoxycarbonyl-1,2-benzoisoxane Azole (0.20 g) gave the title compound (0.16 g, 98%).

Melting point: 211-213°C;

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1718, 1625, 1610, 1544;

NMR spectrum (DMSO-d ₆ ) δppm: 3.37 (2H, q, J=5.1Hz), 3.91 (3H, s),

4.63 (2H, t, J = 5.1Hz), 7.80 (1H, d, J = 8.8Hz), 8.26 (1H, dd, J = 8.8Hz, J = 1.6Hz),

8.44 (1H, d, J=1.6Hz). Example 43 3-(2-aminoethoxy)-5-methylamino-1,2-benzisoxazole dihydrochloride and 3-(2-amino Ethoxy)-5-dimethylamino-1,2-benzisoxazole dihydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-methylamino -1,2-Benzisoxazole and 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-dimethylamino-1,2-benzisoxazole

Under stirring at 5°C, add 5-amino-3-(2-(N-tert-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole (0.88g) to a tetrahydrofuran (10ml) solution Sodium borohydride (0.66g) was added, a solution of 37% aqueous formaldehyde (0.99g) and 3M sulfuric acid (1.0ml) in tetrahydrofuran (10ml) was added dropwise, and stirred at 5°C for 15 minutes. After stirring at room temperature for 1.5 hours, the reaction mixture was cooled to 5°C, 37% aqueous formaldehyde (3.0 g) and sodium borohydride (0.66 g) were added and stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice water (100ml) and extracted with ethyl acetate (twice, 50ml each). The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (4/1) as eluent to obtain 3-(2-(N-tert-butoxycarbonylamino)ethoxy )-5-methylamino-1,2-benzisoxazole (0.49g, 53%) and 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-dimethylamino-1 , 2-Benzisoxazole (0.14 g, 15%).

Data on 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-methylamino-1,2-benzisoxazole.

Melting point: 122-123°C;

IR spectrum (KBr) v _max cm ^-1 : 3392, 3317, 1695, 1673, 1636, 1611, 1548,

1538, 1523;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 2.88 (3H, s), 3.64 (2H, q, J=5.1Hz),

3.79(1H, brs), 4.49(2H, t, J=5.1Hz), 4.99(1H, brs), 6.64(1H, d, J=2.3Hz),

6.87 (1H, dd, J=8.9Hz, J=2.3Hz), 7.23 (1H,d, J=8.9Hz).

Data on 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-dimethylamino-1,2-benzisoxazole.

IR spectrum (KBr) v _max cm ^-1 : 3387, 2979, 2934, 1703, 1547, 1526, 1507;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 2.97 (6H, s), 3.65 (2H, m),

4.49 (2H, t, J = 5.1Hz), 4.99 (1H, brs), 6.78 (1H, d, J = 2.4Hz),

7.10 (1H, dd, J=9.2Hz, J=2.4Hz), 7.30 (1H, d, J=9.2Hz). (b) 3-(2-(aminoethoxy)-5-methylamino-1 , 2-Benzisoxazole dihydrochloride

Reaction and treatment according to the similar method described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino) ethoxy)-5-methylamino-1,2-benzisoxazole (0.30 g) yielded the title compound (0.27 g, 99%).

Melting point: 240-250°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3030, 2961, 2889, 2841, 2756, 2720, 2683,

2646, 2609, 2579, 2535, 2506, 2479, 2421, 2379, 1623, 1604, 1567,

1544, 1528;

NMR spectrum (DMSO-d ₆ ) δppm: 2.84 (3H, s), 3.34 (2H, q, J=5.1Hz),

4.61 (2H, t, J = 5.1Hz), 7.43 (1H, brs), 7.49 (1H, d.J = 8.9Hz), 7.64 (1H, d, J = 8.9Hz),

8.34(3H,brs).(c) 3-(2-(aminoethoxy)-5-dimethylamino-1,2-benzisoxazole dihydrochloride

According to the similar reaction and treatment described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-dimethylamino-1,2-benzoisoxane azole to obtain the title compound.

Melting point: 150-160°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3500-3200, 3100-2800, 2700-2400, 1626,

1551, 1467, 1434;

NMR spectrum (DMSO-d ₆ ) δppm: 3.06 (6H, s),

3.34(2H, dd, J=10.6Hz, J=5.5Hz), 4.62(2H, t, J=5.5Hz), 7.8-7.5(3H, m),

8.37 (2H, brs). Example 44 3-(2-aminoethoxy)-5-difluoromethoxy-1,2-benzisoxazole hydrochloride (a) 5-hydroxyl-3-( 2-(N-tert-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole

The title compound (0.60 g, 62%) was obtained from 3,5-dihydroxy-1,2-benzisoxazole (0.50 g) by reacting and treating in a similar manner as described in Example 1(e). .

Melting point: 152-153°C;

IR spectrum (KBr) v _max cm ^-1 : 3286, 1672, 1543, 1529;

NMR spectrum (CDCl ₃ ) δppm: 1.38 (9H, s), 3.40 (2H, q, J=5.1Hz),

434 (2H, t, J = 5.1Hz), 6.88 (1H, d, J = 2.5Hz), 7.08 (1H, dd, J = 8.9Hz, J = 2.5Hz),

7.42(1H, d, J=8.9Hz), 9.68(1H, s).(b) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-difluoromethoxy-1 , 2-Benzisoxazole

To a solution of 5-hydroxy-3-(2-(N-tert-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole (100 mg) in dimethylformamide (4 ml) was added sodium methoxide (90 mg) and the mixture was stirred at room temperature for 10 minutes, then bubbled with chlorodifluoromethane gas for 20 minutes. The reaction mixture was poured into ice water (30 ml), extracted with ethyl acetate (twice, 30 ml each), and the combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (9/1) as eluent to obtain the title compound (19 mg, 16%) as a colorless powder.

Melting point: 155-156°C;

IR spectrum (KBr) v _max cm ^-1 : 3322, 1699, 1683, 1541;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.65 (2H, q, J=5.1Hz),

4.51(2H, t, J=5.1Hz), 4.94(1H.brs), 6.52(1H, t, J=73.4Hz), 7.30-7.50(3H, m).(c) 3-(2-aminoethyl Oxy)-5-difluoromethoxy-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-difluoromethoxy-1,2-benzo Isoxazole (25 mg) yielded the title compound (20 mg, 95%).

Melting point: 162-164°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1618, 1599, 1544, 1497;

NMR spectrum (DMSO-d ₆ ) δppm: 3.34 (2H, q, J=5.1Hz), 4.63 (2H, t, J=5.1Hz),

4.62 (1H, brs), 7.27 (1H, d, J=73.6Hz), 7.54 (1H, dd, J=9.0Hz, J=2.3Hz),

7.58 (1H, d, J=2.3Hz), 7.75 (1H, d, J=9.0Hz), 8.29 (3H, brs). Example 45 3-(2-aminoethoxy)-7-amino-1, 2-Benzisoxazole dihydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-nitro-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 1 (e), the title compound (2.20 g, 68 %).

Melting point: 116-117°C;

IR spectrum (KBr) v _max cm ^-1 : 3359, 3307, 1718, 1700, 1691, 1628, 1604,

1553;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.67 (2H, q, J=5.1Hz),

4.57 (2H, t, J = 5.1Hz), 4.93 (1H, brs), 7.46 (1H, t, J = 8.1Hz), 7.99 (1H, d, J = 8.1Hz),

8.41(1H, d, J=8.1Hz).(b) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-amino-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 32 (a), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-nitro-1,2-benzisoxazole (1.50 g) yielded the title compound (1.26 g, 93%).

Melting point: 107-108°C;

IR spectrum (KBr) v _max cm ^-1 : 3438, 3349, 1700, 1640, 1604;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.64 (2H, q, J=5.1Hz), 4.03 (2H, s),

4.50(2H,t,J=5.1Hz), 4.98(1H,brs), 6.79(1H,d,J=7.9Hz), 7.00(1H,d,J=7.9Hz),

7.07(1H, t, J=7.9Hz).(c) 3-(2-aminoethoxy)-7-amino-1,2-benzisoxazole dihydrochloride

React and handle according to the similar method described in embodiment 1 (f), by 3-(2-(N-tert-butoxycarbonylamino) ethoxy)-7-amino-1,2-benzisoxazole ( 0.26 g) yielded the title compound (0.23 g, 98%).

Melting point: 185-195°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 3026, 2870, 2583, 1640, 1611,

1582, 1553, 1525, 1509;

NMR spectrum (DMSO-d ₆ ) δppm: 3.33 (2H, q, J=5.1Hz), 4.59 (2H, t, J=5.1Hz),

6.88 (1H, d, J = 7.9Hz), 6.97 (1H, d, J = 7.9Hz), 7.10 (1H, t, J = 7.9Hz), 8.33 (3H, brs). Example 463-(2- Aminoethoxy)-7-carboxy-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 18 (a), and then reaction and treatment according to the method of Example 1 (e), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)- 1,2-Benzisoxazole (0.28g) gave the title compound (0.036g, 14%).

Melting point: 123-126°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3140, 3081, 3024, 2960, 2896, 1714, 1620,

1615, 1553, 1548, 1495;

NMR spectrum (DMSO-d ₆ ) δppm: 3.36 (2H, t, J=5.1Hz), 4.65 (2H, t, J=5.1Hz),

7.53 (1H, t, J = 7.1Hz), 8.05 (1H, d, J = 7.1Hz), 8.18 (1H, d, J = 7.1Hz),

8.32 (3H, brs). Example 47 3-(2-aminoethoxy)-5-hydroxyl-1,2-benzisoxazole hydrochloride

React and handle according to the similar method described in embodiment 1 (f), by 3-(2-(N-tert-butoxycarbonylamino) ethoxy)-5-hydroxyl-1,2-benzisoxazole ( 0.20 g) yielded the title compound (0.16 g, 97%).

Melting point: 205-209°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3467, 3388, 3112, 3024, 2932, 1617, 1541,

1528, 1503;

NMR spectrum (DMSO-d ₆ ) δppm: 3.32 (2H, t, J=5.1Hz), 4.57 (2H, t, J=5.1Hz),

7.01 (1H, d, J = 2.5Hz), 7.13 (1H, dd, J = 9.0Hz, J = 2.5Hz), 7.45 (1H, d, J = 9.0Hz),

8.26 (3H, brs), 9.84 (1H, s). Example 48 3-(2-aminoethoxy)-5-acetoxy-1,2-benzisoxazole hydrochloride (a) 5- Acetoxy-3-(2-(N-tert-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole

Under stirring at 5°C, to a solution of 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-hydroxy-1,2-benzisoxazole (100mg) in tetrahydrofuran (5ml) was added Triethylamine (44 mg) and acetyl chloride (34 mg), and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture of Party A was poured into ice water (40ml), extracted with ethyl acetate (twice, 40ml each), and the combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (9/1) as eluent to obtain the title compound (101 mg, 88%) as a colorless powder.

Melting point: 108-110°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3346, 1767, 1705, 1626, 1618, 1541, 1529;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 2.34 (3H, s), 3.63 (2H, q, J=5.1Hz),

4.50(2H, t, J=5.1Hz), 4.94(1H, brs), 7.25(1H, dd.J=9.0Hz, J=2.2Hz),

7.39 (1H, d, J = 2.2Hz), 7.43 (1H, d, J = 9.0H, z). (b) 3-(2-aminoethoxy)-5-acetoxy-1,2- Benzisoxazole Hydrochloride

According to the similar reaction and treatment described in Example 1 (f), from 5-acetoxy-3-(2-(N-tert-butoxycarbonylamino)ethoxy)-1,2-benzoisoxane Azole (80 mg) yielded the title compound (59 mg, 98%).

Melting point: 168-170°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3064, 3002, 2962, 2891, 2741, 1748, 1726,

1618, 1592, 1545, 1510;

NMR spectrum (DMSO-d ₆ ) δppm: 2.31 (3H, s), 3.31 (2H, q, J=5.1Hz),

4.62 (2H, t, J = 5.1Hz), 7.46 (1H, dd, J = 9.0Hz, J = 2.2Hz), 7.55 (1H, d, J = 2.2Hz),

7.71 (1H, d, J=9.0Hz), 8.27 (3H, brs). Example 49 3-(2-aminoethoxy)-7-methylamino-1,2-benzisoxazole dihydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-methylamino-1,2-benzisoxazole

Reaction and treatment according to the similar method described in Example 43 (a), from 7-amino-3-(2-(N-tert-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole ( 0.88 g) yielded the title compound (0.12 g, 13%).

Melting point: 162-164°C;

IR spectrum (KBr) v _max cm ^-1 : 3346, 3312, 1709, 1639, 1626, 1550, 1514;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 2.99 (3H, d, J=5.0Hz),

3.63(2H, q, J=5.1Hz), 3.63(1H, q, J=5.0Hz), 4.49(2H, t, J=5.1Hz), 4.98(1H, brs),

6.64 (1H, d, J = 7.8Hz), 6.92 (1H, d, J = 7.8Hz), 7.15 (1H, t, J = 7.8Hz). (b) 3-(2-Aminoethoxy)- 7-Methylamino-1,2-Benzisoxazole Dihydrochloride

Reaction and treatment according to the similar method described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino) ethoxy)-7-methylamino-1,2-benzisoxazole (80 mg) yielded the title compound (72 mg, 99%).

Melting point: 171-181°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3026, 2965, 2912, 2866, 2786, 2730, 2638,

2600, 1573, 1546, 1504;

NMR spectrum (DMSO-d ₆ ) δppm: 2.82 (3H, s), 3.33 (2H, q, J=5.1Hz),

4.59 (2H, t, J = 5.1Hz), 6.65 (1H, d, J = 7.9Hz), 6.89 (1H, d, J = 7.9Hz),

7.16 (1H, t, J=7.9Hz), 8.34 (3H, brs). Example 50 5-amino-3-(2-aminoethoxy)-1,2-benzisoxazole dihydrochloride ( a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-nitro-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 1 (e), the title compound (3.60 g, 74 %).

Melting point: 136-137°C;

IR spectrum (KBr) v _max cm ^-1 : 3346, 1688, 1624, 1555, 1531;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.67 (2H, q, J=5.1Hz),

4.55(2H, t, J=5.1Hz), 4.95(1H, brs), 7.56(1H, d, J=9.2Hz),

8.46(1H, dd, J=9.2Hz, J=2.2Hz), 8.62(1H, d, J=2.2Hz).(b) 5-amino-3-(2-(N-tert-butoxycarbonylamino) Ethoxy)-1,2-Benzisoxazole

According to the similar reaction and treatment described in Example 32 (a), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-nitro-1,2-benzisoxazole (2.00 g) yielded the title compound (1.65 g, 91%).

Melting point: 134-135°C;

IR spectrum (KBr) v _max cm ^-1 : 3470, 3442, 3384, 3360, 3325, 3276, 1699,

1639;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.63 (2H, q, J=5.1Hz), 3.70 (2H, s),

4 47 (2H, t, J = 5.1Hz), 4.95 (1H, brs), 6.83 (1H, d, J = 2.7Hz),

6.92 (1H, dd, J=8.9Hz, J=2.7Hz), 7.23 (1H, d, J=g.9Hz). (c) 5-amino-3-(2-aminoethoxy)-1, 2-Benzisoxazole dihydrochloride

React and handle according to the similar method described in embodiment 1 (f), by 5-amino-3-(2-(N-tert-butoxycarbonylamino) ethoxy)-1,2-benzisoxazole ( 0.24 g) yielded the title compound (0.21 g, 99%).

Melting point: 182-202°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3428, 3379, 2963, 2859, 2726, 2665, 2581,

1656, 1637, 1628, 1609, 1549, 1507;

NMR spectrum (DMSO-d ₆ ) δppm: 3.46 (2H, q, J = 5.1 Hz),

4.63 (2H, t, J = 5.1Hz), 7.57 (1H, dd, J = 8.9Hz, J = 2.0Hz), 7.67 (1H, d, J = 2.0Hz),

7.93 (1H, d, J=8.9Hz), 8.35 (3H, brs). Example 51 3-(2-aminoethoxy)-4,7-dimethyl-1,2-benzisoxazole salt Acid salt (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4,7-dimethyl-1,2-benzisoxazole

3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-methyl-1,2-benzisoxazole (0.15g) in tetrahydrofuran was stirred under a nitrogen atmosphere at -70°C (5ml) solution was added dropwise with butyllithium (0.7ml, 1.6M solution in hexane), and the mixture was stirred at the same temperature for 10 minutes, and then the temperature was raised to 0°C. After cooling the reaction mixture to -70°C, iodomethane was added and the temperature was allowed to rise to 0°C. The reaction mixture was dissolved in ice water (40ml), extracted with ethyl acetate (twice, 40ml each), and the combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (9/1) as eluent to obtain the title compound (0.12 g, 80%) as a colorless powder.

Melting point: 78-79°C;

IR spectrum (KBr) v _max cm ^-1 : 3352, 1694, 1604, 1543, 1517;

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 2.44 (3H, s), 2.56 (3H, s),

4.26 (2H, q, J = 5.1Hz), 4.49 (2H, t, J = 5.1Hz), 4.90 (1H, brs), 6.89 (1H, d, J = 7.3Hz),

7.15 (1H, d, J=7.3Hz). (b) 3-(2-aminoethoxy)-4,7-dimethyl-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4,7-dimethyl-1,2-benzo Isoxazole (0.10 g) gave the title compound (0.08 g, quantitative).

Melting point: 222-225°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3300-2400, 1601, 1561, 1542, 1511;

NMR spectrum (DMSO-d ₆ ) δppm: 2.40 (3H, s), 2.57 (3H, s),

3.35(2H, t, J=5.1Hz), 4 60(2H, t, J=5.1Hz), 7.01(1H, d, J=7.3Hz),

7.31 (1H, d, J=7.3Hz), 8.31 (3H, brs) Example 52 3-(2-aminoethoxy)-4-methoxy-1,2-benzisoxazole hydrochloride ( a) Methyl 2-fluoro-6-methoxybenzoate

Under stirring at room temperature, anhydrous potassium carbonate (6.00 g) and methyl iodide (6.0 ml) were added to a solution of 6-fluorosalicylic acid (5.00 g) in dimethylformamide (50 ml), followed by vigorous stirring at room temperature 12 hours. After the reaction was completed, the reaction mixture was diluted with ether, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (5.80 g, 98%) as an oil.

NMR spectrum (CDCl ₃ ) δppm: 3.86 (3H, s), 3.93 (3H, s), 6.70-6.80 (2H, m),

7.28-7.37 (1H, m). (b) 2-fluoro-6-methoxyphenhydroxamic acid

The title compound (44%) was prepared from methyl 2-fluoro-6-methoxybenzoate and hydroxylamine hydrochloride by reacting and working up in a manner similar to that described in Example 1(b).

NMR spectrum (CDCl ₃ +MeOH-d ₄ ) δppm: 3.92 (3H, s), 6.75-6.86 (2H, m),

7.35-7.45 (1H, m). (c) 3-Hydroxy-4-methoxy-1,2-benzisoxazole

2-Fluoro-6-methoxyphenhydroxamic acid (2.55g) and potassium hydroxide (4.50g) were dissolved in butanol (25ml) and refluxed for 4 hours. After the reaction was completed, the reaction mixture was made acidic, extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from isopropyl ether to obtain the title compound (2.05 g, 90%).

Melting point: 183-185°C;

NMR spectrum (CDCl ₃ ) δppm: 4.02 (3H, s), 6.65 (1H, d, J=8.2Hz),

6.99 (1H, d, J = 8.2Hz), 7.50 (1H, t, J = 8.2Hz). (d) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-methoxy-1,2-benzisoxazole

The title compound (81%) was obtained from 3-hydroxy-4-methoxy-1,2-benzisoxazole by reaction and work-up similar to that described in Example 1(e).

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.65 (2H, s), 3.96 (3H, s),

4.50 (2H, t, J = 5.1Hz), 5.06 (1H, brs), 6.61 (1H, d, J = 8.2Hz), 7.02 (1H, d, J = 8.2Hz),

7.43 (1H, t, J=8.2Hz). (e) 3-(2-aminoethoxy)-4-methoxy-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-methoxy-1,2-benzoisoxane Azole afforded the title compound (82%).

Melting point: 193-197°C;

IR spectrum (KBr) v _max cm ^-1 : 3435, 3220, 2960, 1630, 1615, 1535, 1505;

NMR (DMSO-d ₆ ) δppm: 3.34 (2H, t, J=5.2Hz), 3.92 (3H, s),

4.60 (2H, t, J = 5.2Hz), 6.86 (1H, d, J = 8.4Hz), 7.17 (1H, d, J = 8.4Hz),

7.58 (1H, t, J=8.4Hz). Example 53 3-(2-aminoethoxy)-4-methoxy-7-methyl-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-methoxy-1,2-benzoisoxane azole to obtain the title compound.

Melting point: 208-211°C;

IR spectrum (KBr) v _max cm ^-1 : 3160, 2840, 1640, 1620, 1540, 1520, 1510;

NMR spectrum (DMSO-d ₆ ) δppm: 2.35 (3H, s), 3.33 (2H, t, J=5.4Hz),

3.89(3H, s), 4.59(2H, t, J=5.4Hz), 6.75(1H, d, J=8.1Hz), 7.37(1H, d, J=8.1Hz),

8.30(3H, brs). Example 54 3-(2-aminoethoxy)-4-fluoro-1,2-benzisoxazole hydrochloride (a) 2,6-difluorobenzohydroxamic acid

The title compound (65%) was prepared from methyl 2,6-difluorobenzoate and hydroxylamine hydrochloride by reacting and working up in a manner similar to that described in Example 1(b).

NMR spectrum (DMSO-d ₆ ) δppm: 7.14-7.25 (2H, m), 7.50-7.60 (1H, m),

9.40 (1H, brs), 11.15 (1H, brs). (b) 3-hydroxy-4-fluoro-1,2-benzisoxazole

The title compound (36%) was prepared from 2,6-difluorophenylhydroxamic acid by reaction and workup similar to that described in Example 52(c).

Melting point: 175-178°C;

NMR spectrum (DMSO-d ₆ ) δppm: 7.09 (1H, t, J=8.5Hz), 7.40 (1H, d, J=8.5Hz),

7.57-7.65 (1H, m). (c) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-fluoro-1,2-benzisoxazole

The title compound (67%) was obtained from 3-hydroxy-4-fluoro-1,2-benzisoxazole by reaction and work-up similar to that described in Example 1(e).

NMR spectrum (CDCl ₃ ) δppm: 1.47 (9H, s), 3.65 (2H, m), 4.51 (2H, t, J=5.1Hz),

4.90-5.06(1H, brs), 6.91(1H, t, J=8.5Hz), 7.23(1H, t, J=8.5Hz), 7.44-7.52(1H, m).(d)3-(2- Aminoethoxy)-4-fluoro-1,2-benzisoxazole hydrochloride

According to the reaction and treatment similar to that described in Example 1(f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-fluoro-1,2-benzisoxazole The title compound (75%) was obtained.

Melting point: 230-233°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3435, 2970, 1635, 1620, 1545, 1520, 1510;

NMR spectrum (DMSO-d ₆ ) δppm: 3.34 (2H, t, J=5.2Hz), 4.66 (2H, t, J=5.2Hz),

7.21 (1H, t, J=8.3Hz), 7.53 (1H, d, J=8.3Hz), 7.68-7.74 (1H, m), 8.35 (3H, brs). Example 553-(2-Aminoethoxy Base)-4-fluoro-5-methyl-1,2-benzisoxazole hydrochloride and 3-(2-aminoethoxy)-4-fluoro-7-methyl-1,2-benzene Isoxazole hydrochloride

According to Example 51(a), followed by reaction and treatment similar to that described in Example 1(f), 3-(2-aminoethoxy)-4-fluoro-1,2-benzisoxazole 3-(2-aminoethoxy)-4-fluoro-5-methyl-1,2-benzisoxazole hydrochloride and 3-(2-aminoethoxy)-4-fluoro- 7-methyl-1,2-benzisoxazole hydrochloride. (a) Data concerning 3-(2-aminoethoxy)-4-fluoro-5-methyl-1,2-benzisoxazole hydrochloride.

Melting point: 201-208°C;

IR spectrum (KBr) v _max cm ^-1 : 3430, 3305, 2840, 1645, 1615, 1540, 1515;

NMR spectrum (DMSO-d ₆ ) δppm: 2.32 (3H, s), 3.34 (2H, q, J=5.0Hz),

4.64(2H, t, J=5.0Hz), 7.42(2H, d, J=8.4Hz), 7.60(1H, t, J=8.4Hz), 8.27(3H, brs).(b)3-(2 -Aminoethoxy)-4-fluoro-7-methyl-1,2-benzisoxazole hydrochloride.

Melting point: 196-202°C;

IR spectrum (KBr) v _Max cm ^-1 : 2975, 1635, 1550, 1520;

NMR spectrum (DMSO-d ₆ ) δppm: 2.42 (3H, s), 3.35 (2H, t, J=5.2Hz),

4.65(2H, t, J=5.2Hz), 7.10(1H, t, J=8.9Hz), 7.47-7.51(1H, m), 8.32(3H, brs).Example 563-(2-Aminoethylsulfur Base)-5-chloro-7-methyl-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-chloro- 7-Methyl-1,2-Benzisoxazole

According to the similar reaction and treatment described in Example 17 (b), 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5-chloro-1,2-benzisoxazole ( 0.20 g) yielded the title compound (0.13 g, 62%).

NMR spectrum (CDCl ₃ ) δppm: 1.44 (9H, s), 2.51 (3H, s), 3.40 (2H, t, J=6.3Hz),

3.58 (2H, q, J=6.3Hz), 5.07 (1H, brs), 7.29 (1H., s), 7.36 (1H, s). (b) 3-(2-Aminoethylthio)-5-chloro-7-methyl-1,2-benzisoxazole hydrochloride

According to the reaction and treatment of the similar method described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5-chloro-7-methyl-1,2-benzene Isoxazole (0.12 g) gave the title compound (0.10 g, quantitative).

Melting point: 205-208°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 2966, 2927, 2848, 2802, 1481;

NMR spectrum (DMSO-d ₆ ) δppm: 2.50 (3H, s), 3.23 (2H, t, J=6.9Hz),

3.53 (2H, t, J=6.9Hz), 7.62 (1H, s), 7.74 (1H, s), 8.19 (3H, brs). Example 573-(2-aminoethylthio)-5-chloro- 7-cyano-1,2-benzoisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-chloro-7-carboxy-1,2 -Benzisoxazole

According to the similar reaction and treatment described in Example 18 (a), 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5-chloro-1,2-benzisoxazole ( 0.51 g) yielded the title compound (0.42 g, 72%). (b) 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-chloro-7-carbamoyl-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 18 (b), from 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-chloro-7-carboxy-1,2-benzo Isoxazole (0.20 g) gave the title compound (0.17 g, 85%).

IR spectrum (KBr) v _max cm ^-1 : 3471, 3354, 3143, 1693, 1678;

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 3.45 (2H, t, J=6.1Hz),

3.59(2H, q, J=6.1Hz), 4.96(1H, brs), 5.97(1H, brs), 7.12(1H, brs), 7.73(1H, s),

8.34(1H,s).(c)3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-chloro-7-cyano-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 19 (a), from 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5-chloro-7-carbamoyl-1,2- Benzisoxazole (0.15 g) gave the title compound (0.13 g, 90%).

IR spectrum (KBr) v _max cm ^-1 : 3366, 2240, 1685;

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 3.46 (2H, t, J=6.2Hz),

3.60(2H, q, J=6.2Hz), 4.96(1H, brs), 7.81(1H, s), 7.84(1H, s).(d) 3-(2-Aminoethylthio)-5-chloro -7-cyano-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5-chloro-7-cyano-1,2-benzene Isoxazole (0.12 g) gave the title compound (0.10 g, quantitative).

Melting point: 178-181°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3432, 3038, 2990, 2235, 1607, 1598, 1588;

NMR spectrum (DMSO-d ₆ ) δppm: 3.25 (2H, t, J=7.0Hz), 3.57 (2H, t, J=7.0Hz),

8.23 (3H, brs), 8.42 (1H, s), 8.49 (1H, s). Example 58 3-(2-Aminoethoxy)-5-chloropyrido[3,2-d]isoxazole hydrochloride (a) Methyl 2,5-dichloronicotinate

Under ice-cooling and stirring, 2,5-dichloronicotinoyl chloride (5.0 g) was dissolved in methanol (30 ml), and stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was dissolved in ether and washed with saturated aqueous sodium bicarbonate and brine. The extract was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (30/1) as eluent to obtain the title compound (4.2 g, 86%).

NMR spectrum (CDCl ₃ ) δppm: 3.98 (3H, s), 8.16 (1H, s), 8.48 (1H, s). (b) 2,5-dichloropyridine-3-carboxyxamic acid

The title compound (3.3 g, 79%) was prepared from methyl 2,5-dichloronicotinate (4.2 g) by reacting and working up in a similar manner as described in Example 10(b).

IR spectrum (KBr) v _max cm ^-1 : 3187, 3073, 3058, 2985, 2906, 2851, 1661,

1575, 1553;

NMR spectrum (DMSO-d ₆ ) δppm: 8.11 (1H, s), 8.58 (1H, s), 9.50 (1H, s),

11.40 (1H, s). (c) 3-Hydroxy-5-chloropyrido[3,2-d]isoxazole

The title compound (0.82 g, 66%) was obtained from 2,5-dichloropyridine-3-carboxyxamic acid (1.5 g) by reacting and working up in a similar manner as described in Example 10(c).

IR spectrum (KBr) v _max cm ^-1 : 3193, 3166, 3069, 3055, 3003, 2919, 2821, 2783, 2734,

2689, 2633, 2587, 2550, 1697, 1615, 1602, 1554, 1508;

NMR spectrum (DMSO-d ₆ ) δppm: 8.40 (1H, s), 8.63 (1H, s), 12.90 (1H, brs). (d) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloropyrido[3,2-d]isoxazole

The title compound (0.27 g, 73%) was obtained from 3-hydroxy-5-chloropyrido[3,2-d]isoxazole by reaction and workup similar to that described in Example 1(e).

IR spectrum (KBr) v _max cm ^-1 : 3360, 1709, 1701, 1599, 1537, 1525;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.64 (2H, q, J=5.2Hz),

4.52 (2H, t, J=5.2Hz), 4.90 (1H, brs), 8.03 (1H, s), 8.54 (1H, s). (e) 3-(2-Aminoethoxy)-5-chloropyrido[3,2-d]isoxazole hydrochloride

According to the similar reaction and treatment described in Example 1(f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloropyrido[3,2-d]isoxane Azole (0.21 g) gave the title compound (0.19 g, quantitative).

Melting point: 225-230°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3065, 3036, 2978, 2900, 1604, 1598, 1535;

NMR spectrum (DMSO-d ₆ ) δppm: 3.34 (2H, t, J=5.0Hz), 4.64 (2H, t, J=5.0Hz),

8.25 (3H, brs), 8.50 (1H, s), 8.76 (1H, s). Example 59 3-(2-aminoethylthio)-5-chloropyrido[3,2-d]isoxazole hydrochloride (a) 3,5-dichloropyrido[3,2-d]iso Oxazole

According to the reaction and treatment similar to that described in Example 16, the title compound (0.21 g, 73%) was obtained from 5-chloro-3-hydroxypyrro[3,2-d]isoxazole (0.27 g) .

NMR spectrum (CDCl ₃ ) δppm: 8.08 (1H, s), 8.64 (1H, s). (b) 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-chloropyrido[3,2-d]isoxazole

According to the similar reaction and treatment described in Example 26 (b), the title compound (0.12 g, 71 %).

IR spectrum (KBr) v _max cm ^-1 : 3369, 1688, 1530;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.44 (2H, t, J=6.3Hz),

3.59 (2H, q, J=6.3Hz), 4.97 (1H, brs), 7.95 (1H, s), 8.57 (1H, s). (c) 3-(2-Aminoethylthio)-5-chloropyrido[3,2-d]isoxazole hydrochloride

According to the similar reaction and treatment described in Example 1(f), 3-(2-(N-tert-butoxycarbonylamino)ethylthio)-5-chloropyrido[3,2-d]isoxane Azole (0.10 g) gave the title compound (0.08 g, quantitative).

Melting point: 194-198°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3040, 3001, 2909, 1586, 1515;

NMR spectrum (DMSO-d ₆ ) δppm: 3.24 (2H, t, J=7.1Hz), 3.55 (2H, t, J=7.1Hz),

8.17 (3H, brs), 8.69 (1H, s), 8.79 (1H, s). Example 60 3-(2-aminoethoxy)-4-methoxycarbonyl-7-methyl-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxy Carbonylamino)ethoxy)-4-methoxycarbonyl-7-methyl-1,2-benzisoxazole

Reaction and treatment according to the similar method described in Example 22 (b), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-methyl-1,2-benzisoxazole The title compound was obtained (91%).

Melting point: 62-64°C;

IR spectrum (KBr) v _max cm ^-1 : 3380, 1715, 1703, 1621, 1591, 1534, 1513;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 2.56 (3H, s), 3.66 (2H, q),

3.97(3H, s), 4.51(2H, t, J=5.1Hz), 5.33(1H, brs), 7.35(1H, d, J=7.6Hz),

7.78 (1H, d, J=7.6Hz). (b) 3-(2-aminoethoxy)-4-methoxycarbonyl-7-methyl-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-methoxycarbonyl-7-methyl-1,2 - Benzisoxazole The title compound was obtained (97%).

Melting point: 200-202°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3184, 3003, 2953, 1699, 1608, 1591, 1534,

1511;

NMR spectrum (DMSO-d ₆ ) δppm: 2.53 (3H, s), 3.34 (2H, t, J=5.1Hz),

3.91(3H, s), 4.61(2H, t, J=5.1Hz), 7.59(1H, d, J=7.5Hz), 7.76(1H, d, J=7.5Hz),

8.19 (3H, brs). Example 61 3-(2-aminoethoxy)-4-carbamoyl-7-methyl-1,2-benzisoxazole hydrochloride (a)3-(2 -(N-tert-butoxycarbonylamino)ethoxy)-4-carbamoyl-7-methyl-1,2-benzisoxazole

Reaction and treatment according to the similar method described in Example 23 (a), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-methyl-1,2-benzisoxazole The title compound was obtained (83%).

Melting point: 140-141°C;

IR spectrum (KBr) v _max cm ^-1 : 3451, 3351, 3199, 1705, 1675, 1618, 1585,

1539, 1525, 1509;

NMR spectrum (CDCl ₃ ) δppm: 1.43 (9H, s), 2.56 (3H, s),

3.70 (2H, q, J = 5.1Hz), 4.61 (2H, t, J = 5.1Hz), 4.94 (1H, brs), 5.89 (1H, brs),

7.41 (1H, d, J = 7.6Hz), 7.80 (1H, brs), 8.06 (1H, d, J = 7.6Hz). (b) 3-(2-aminoethoxy)-4-carbamoyl -7-Methyl-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-carbamoyl-7-methyl-1,2 - Benzisoxazole The title compound was obtained (99%).

Melting point: 202-205°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3435, 3347, 3293, 3203, 2950, 1901, 1687,

1659, 1608, 1581, 1544, 1512;

NMR spectrum (DMSO-d ₆ ) δppm: 2.50 (3H, s), 3.34 (2H, t, J=5.1Hz),

4.64 (2H, t, J=5.1Hz), 7.53 (2H, s), 7.64 (1H, brs), 7.92 (1H, brs), 8.22 (3H, brs). Embodiment 623-(2-Aminoethoxy Base) -4-cyano-7-methyl-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-cyano yl-7-methyl-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 24 (a), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-carbamoyl-7-methyl-1,2 - Benzisoxazole The title compound was obtained (95%).

Melting point: 84-85°C;

IR spectrum (KBr) v _max cm ^-1 : 3452, 3397, 2231, 1716, 1597, 1552, 1541,

1509;

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 2.59 (3H, s),

3.68 (2H, q, J = 5.1Hz), 4.54 (2H, t, J = 5.1Hz), 5.10 (1H, brs), 7.40 (1H, d, J = 7.4Hz),

7.54 (1H, d, J=7.4Hz). (b) 3-(2-aminoethoxy)-4-cyano-7-methyl-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-cyano-7-methyl-1,2- Benzisoxazole yielded the title compound (96%).

Melting point: 208-211°C;

IR spectrum (KBr) v _max cm ^-1 : 3099, 3036, 2966, 2908, 2873, 2850, 2754,

2733, 2232, 1598, 1542, 1514;

NMR spectrum (DMSO-d ₆ ) δppm: 2.56 (3H, s), 3.39 (2H, t, J=5.1Hz),

4.71 (2H, t, J=5.1Hz), 7.68 (1H, d.J=7.5Hz), 7.87 (1H, d, J=7.5Hz), 8.26 (3H, brs). Example 633-(2-aminoethyl Oxy)-7-methyl-4-methylthio-1,2-benzisoxazole hydrochloride (a)3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7 -Methyl-4-methylthio-1,2-benzisoxazole

Under a nitrogen atmosphere at -70°C and stirring, 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-methyl-1,2-benzisoxazole (0.15g) in tetrahydrofuran ( 20 ml) was added dropwise to butyllithium (0.75 ml, 1.6M hexane solution), and the mixture was stirred at the same temperature for 15 minutes, followed by the addition of dimethyl disulfide (0.11 g). The reaction mixture was poured into ice water (40 ml), extracted with ethyl acetate (twice, 40 ml each), and the combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (9/1) as eluent to obtain the title compound (0.15 g, 88%) as a colorless powder.

Melting point: 85-86°C;

IR spectrum (KBr) v _max cm ^-1 : 3376, 1699, 1627, 1589, 1549, 1533;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 2.44 (3H, s), 2.53 (3H, s),

3.66 (2H, q, J = 5.1Hz), 4.49 (2H, t, J = 5.1Hz), 5.07 (1H.brs), 6.86 (1H, d, J = 7.5Hz),

7.22 (1H, d, J=7.5Hz). (b) 3-(2-aminoethoxy)-7-methyl-4-methylthio-1,2-benzisoxazole hydrochloride

React and treat according to the similar method described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-methyl-4-methylthio-1,2 - Benzisoxazole The title compound was obtained (94%).

Melting point: 216-218°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 2940, 2917, 2883, 1629, 1593, 1541, 1508;

NMR spectrum (DMSO-d ₆ ) δppm: 2.39 (3H, s), 2.53 (2H, s),

3.34 (2H, t, J = 5.1Hz), 4.61 (2H, t, J = 5.1Hz), 7.03 (1H, d, J = 7.5Hz),

7.41 (1H, d, J=7.5Hz), 8.26 (3H, brs). Example 64 3-(2-aminoethoxy)-7-chloro-4-methyl-1,2-benzisoxazole Hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-chloro-4-methyl-1,2-benzisoxazole

React and work up in a manner similar to that described in Example 51(a), prepared from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-chloro-1,2-benzisoxazole The title compound was obtained in 93% yield.

IR spectrum (KBr) v _max cm ^-1 : 3355, 1691, 1605, 1551, 1536;

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 2.57 (3H, s),

3.65 (2H, q, J = 5.1Hz), 4.50 (2H, t, J = 5.1Hz), 4.87 (1H, brs), 6.94 (1H, d, J = 7.8Hz),

7.37 (1H, d, J=7.8Hz: ).(b) 3-(2-Aminoethoxy)-7-chloro-4-methyl-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-chloro-4-methyl-1,2-benzene and isoxazole to obtain the title compound in 98% yield.

Melting point: 215-218°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3194, 2967, 2892, 1606, 1540;

NMR spectrum (DMSO-d ₆ ) δppm: 2.60 (3H, s), 3.35 (2H, t, J=5.1Hz),

4.63 (2H, t, J=5.1Hz), 7.17 (1H, d, J=7.7Hz), 7.66 (1H, d, J=7.7Hz), 8.24 (3H, brs). Embodiment 653-(2- Aminoethoxy)-5,7-dichloro-4-methyl-1,2-benzisoxazole hydrochloride (a)3-(2-(N-tert-butoxycarbonylamino)ethoxy )-5,7-dichloro-4-methyl-1,2-benzisoxazole

React and handle according to the similar method described in Example 5 1(a), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5,7-dichloro-1,2-benzo Isoxazole afforded the title compound in 95% yield.

Melting point: 109-111°C;

IR spectrum (KBr) v _max cm ^-1 : 3354, 1697, 1616, 1552, 1528;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 2.59 (3H, s),

3.63 (2H, q, J = 5.1Hz), 4.50 (2H, t, J = 5.1Hz), 4.93 (1H, brs), 7.58 (1H, s). (b) 3-(2-Aminoethoxy )-5,7-dichloro-4-methyl-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5,7-dichloro-4-methyl-1, 2-Benzisoxazole afforded the title compound in 99% yield.

Melting point: 222-225°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3062, 2970, 2897, 2770, 1618, 1596, 1542,

1521;

NMR spectrum (DMSO-d ₆ ) δppm: 2.56 (3H, s), 3.38 (2H, t, J=5.1Hz),

4.62 (2H, t, J = 5.1 Hz), 7.90 (1H, s), 8.28 (3H, brs). Example 66 3-(2-aminoethoxy)-7-carbamoyl-5-chloro-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonyl Amino)ethoxy)-7-carbamoyl-5-chloro-1,2-benzisoxazole

According to Example 18(a), followed by reaction and treatment similar to that described in Example 18(b), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloro-1 , 2-Benzisoxazole to obtain the title compound in 88% yield.

IR spectrum (KBr) v _max cm ^-1 : 3428, 3375, 3297, 3187, 1691, 1658, 1620,

1560, 1531;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.66 (2H, q, J=5.1 Hz),

4.53(2H,t,J=5.1Hz), 4.94(1H,brs), 5.99(1H,brs), 7.08(1H,brs),

7.80 (1H, d, J = 2.1 Hz), 8.31 (1H, d, J = 2.1 Hz). (b) 3-(2-aminoethoxy)-7-carbamoyl-5-chloro-1, 2-Benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-carbamoyl-5-chloro-1,2- Benzisoxazole afforded the title compound in 98% yield.

Melting point: 232-237°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3450, 3339, 3290, 3238, 3164, 3082, 3047, 3011,

2952, 2878, 2847, 2818, 2766, 2688, 1672, 1626, 1608, 1594, 1547,

1520;

NMR spectrum (DMSO-d ₆ ) δppm: 3.47 (2H, t, J=5.1Hz), 4.63 (2H, t, J=5.1Hz),

7.94(1H, brs), 7.97(1H, brs), 8.03(1H, d, J=2.2Hz), 8.05(1H, d, J=2.2Hz),

8.33(3H, brs). Example 67 3-(2-aminoethoxy)-5-chloro-7-cyano-1,2-benzisoxazole hydrochloride (a) 3-(2-( N-tert-butoxycarbonylamino)ethoxy)-5-chloro-7-cyano-1,2-benzisoxazole

According to the similar reaction and treatment described in Example 24 (a), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloro-7-carbamoyl-1,2- Benzisoxazole afforded the title compound in 92% yield.

Melting point: 141-143°C;

IR spectrum (KBr) v _max cm ^-1 : 3364, 2244, 1684, 1609, 1547, 1527;

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 3.62 (2H, q, J=5.1Hz),

4.53(2H,t,J=5.1Hz), 4.90(1H,brs), 7.81(1H,d,J=2.2Hz), 7.88(1H,d,J=2.2Hz).(b)3-(2 -aminoethoxy)-5-chloro-7-cyano-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloro-7-cyano-1,2-benzene and isoxazole to obtain the title compound in 94% yield.

Melting point: 211-214°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3070, 3047, 2943, 2878, 2810, 2769, 2739, 2685,

2637, 2243, 1611, 1586, 1548, 1507;

NMR spectrum (DMSO-d ₆ ) δppm: 3.34 (2H, t, J=5.1Hz), 4.65 (2H, t, J=5.1Hz),

8.32 (1H, d, J = 2.2Hz), 8.39 (3H, brs), 8.48 (1H, d, J = 2.2Hz). Example 68 3-(2-aminoethoxy)pyrido[2,3-d]isoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)pyrido [2,3-d]isoxazole

The title compound was obtained from 3-hydroxypyrido[2,3-d]isoxazole by reacting and working up in a similar manner as described in Example 1(e) in a yield of 63%.

Melting point: 94-95°C;

IR spectrum (KBr) v _max cm ^-1 : 3374, 3247, 1754, 1698, 1678, 1587, 1529;

NMR spectrum (CDCl ₃ ) δppm: 1.44 (9H, s), 3.68 (2H, q, J=5.1Hz),

4.59(2H, t, J=5.1Hz), 5.12(1H, brs), 7.50(1H, dd, J=8.6Hz, J=4.4Hz),

7.81 (1H, dd, J=8.6Hz, J=1.4Hz), 8.68 (1H, dd, J=4.4Hz, J=1.4Hz).(b) 3-(2-Aminoethoxy)pyrido[ 2,3-d]isoxazole hydrochloride

According to the similar reaction and treatment described in Example 1 (f), the obtained compound was obtained from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)pyrido[2,3-d]isoxazole The title compound was obtained in 89% yield.

Melting point: 217-222°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3070, 3020, 2980, 2911, 2870, 2783, 2700, 2658,

2601, 1631, 1586, 1541;

NMR spectrum (DMSO-d ₆ ) δppm: 3.35 (2H, t, J = 5.1 Hz),

4.72 (2H, t, J = 5.1Hz), 7.73 (1H, dd, J = 8.6Hz, J = 4.4Hz), 8.21 (1H, d, J = 8.6Hz),

8.32 (3H, brs), 8.73 (1H, d, J=4.4Hz). Example 69 3-(2-aminoethoxy)-4-trifluoromethylpyrido[3,2-d]isoxazole Hydrochloride (a) 4-trifluoromethylnicotinic acid N-oxide

4-Trifluoromethylnicotinic acid (5.00 g) was dissolved in a solution of acetic acid (20 ml) and 31% hydrogen peroxide (5 ml) and stirred at 100°C for 10 hours. The solvent was distilled off under reduced pressure to obtain the title compound (5.40 g, quantitative) as a solid.

Melting point: 210-215°C (decomposition);

NMR spectrum (CDCl ₃ ) δppm: 7.61 (1H, d, J=6.9Hz), 8.32 (1H, d, J=6.9Hz),

8.56 (1H, s). (b) Methyl 2-chloro-4-trifluoromethylnicotinate

Phosphorus oxychloride (4.0ml) and phosphorus pentachloride (4.0g) were added to 4-trifluoromethylnicotinic acid N-oxide (2.00g) and the mixture was stirred at 100°C for 4 hours. Phosphorus oxychloride was distilled off under reduced pressure. To the residue was added methanol (30 ml) under ice-cooling, followed by stirring at room temperature for 30 minutes. After adding aqueous sodium bicarbonate solution to the reaction mixture, the pH was adjusted to basic, the mixture was extracted with ether and washed with water, and the extract was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using hexane/ethyl acetate (9/1) as eluent to obtain the title compound (310 mg, 14%) as an oil.

NMR spectrum (CDCl ₃ ) δppm: 4.01 (3H, s), 7.54 (1H, d, J=5.3Hz),

8.65 (1H, d, J = 5.3 Hz). (c) 3-Hydroxy-4-trifluoromethylpyrido[3,2-d]isoxazole

At room temperature, an aqueous solution (5 ml) of hydroxylamine hydrochloride (450 mg) and sodium hydroxide (520 mg) was added to 2-chloro-4-trifluoromethylnicotinic acid methyl ester (300 mg), and the mixture was cooled at room temperature Under stirring for 5 days. After dilute aqueous hydrochloric acid was added to the reaction mixture, the pH was adjusted to acidic, and the mixture was extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain the title compound (180 mg, 67%) as a solid.

Melting point: 196-202°C;

NMR spectrum (DMSO-d ₆ ) δppm: 7.81 (1H, d, J=4.9Hz), 8.88 (1H, d, J=4.9Hz),

13.30 (1H, brs). (d) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-trifluoromethylpyrido[3,2-d]isoxazole

According to the similar reaction and treatment described in Example 1 (e), from 3-hydroxyl-4-trifluoromethylpyrido[3,2-d]isoxazole and 2-(N-tert-butoxycarbonylamino ) ethanol to obtain the title compound in 75% yield.

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 3.65 (2H, q, J=5.2Hz),

4.55 (2H, t, J = 5.2Hz), 4.90 (1H, brs), 7.56 (1H, d, J = 4.9Hz), 8.77 (1H, d, J = 4.9Hz). (e)3-(2 -Aminoethoxy)-4-trifluoromethylpyrido[3,2-d]isoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-trifluoromethylpyrido[3,2-d ] isoxazole to obtain the title compound in 96% yield.

Melting point: 203-207°C;

IR spectrum (KBr) v _max cm ^-1 : 3100, 2970, 1600, 1540;

NMR spectrum (DMSO-d ₆ ) δppm: 3.34 (2H, t, J=5.5Hz),

4.71 (2H, t, J=5.5Hz), 7.94 (1H, d, J=4.8Hz), 8.26 (3H, brs), 8.97 (1H, d, J=4.8Hz). Embodiment 703-(2- Aminoethoxy)-7-trifluoromethyl-1,2-benzisoxazole hydrochloride (a) methyl 2-fluoro-3-trifluoromethylbenzoate

The title compound was obtained as an oil from 2-fluoro-3-trifluoromethylbenzoic acid by reacting and working up in a manner similar to that described in Example 52(a).

NMR spectrum (CDCl ₃ ) δppm: 3.96 (3H, s), 7.31 (1H, t, J=5.0Hz),

7.79 (1H, t, J = 5.0 Hz), 8.18 (1 H, t, J = 5.0 Hz). (b) 2-Fluoro-3-trifluoromethylbenzohydroxamic acid

The title compound was prepared from methyl 2-fluoro-3-trifluoromethylbenzoate by reaction and workup similar to that described in Example 52(b).

NMR spectrum (DMSO-d ₆ ) δppm: 7.46 (1H, t, J = 5.0 Hz), 7.82 (2H,). (c) 3-Hydroxy-7-trifluoromethyl-1,2-benzisoxazole

The title compound was obtained as a solid from 2-fluoro-3-trifluoromethylphenylhydroxamic acid by reacting and working up in a manner similar to that described in Example 52(c).

Melting point: 204-207°C;

NMR spectrum (DMSO-d ₆ ) δppm: 7.54 (1H, t, J=7.6Hz), 7.98 (1H, d, J=7.6Hz),

8.09 (1H, d, J=7.7Hz), 12.80 (1H, brs). (d) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-trifluoromethyl-1,2-benzisoxazole

React and handle according to the similar method described in Example 1 (e), from 3-hydroxyl-7-trifluoromethyl-1,2-benzisoxazole and 2-(N-tert-butoxycarbonylamino)ethanol The title compound was obtained as a solid in 65% yield.

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 3.65 (2H, q, J=5.2Hz),

4.54 (2H, t, J = 5.2Hz), 4.52 (1H, brs), 7.39 (1H, t, J = 7.6Hz), 7.79 (1H, d, J = 7.6Hz),

7.85 (1H, d, J=7.6Hz). (e) 3-(2-aminoethoxy)-7-trifluoromethyl-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7-trifluoromethyl-1,2-benziso Oxazole afforded the title compound in 77% yield.

Melting point: 190-194°C;

IR spectrum (KBr) v _max cm ^-1 : 2970, 2905, 1615, 1555, 1510;

NMR spectrum (DMSO-d ₆ ) δppm: 3.37 (2H, t, J = 5.1 Hz),

4.68 (2H, t, J = 5.1Hz), 7.62 (1H, t, J = 7.6Hz), 8.09 (1H, d, J = 7.6Hz),

8.16 (1H, d, J=7.6Hz), 8.44 (3H, brs) Example 71 3-(2-aminoethoxy)-4-chloro-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-chloro-1,2-benzisoxazole

React and process according to the similar method described in Example 1 (e), from 3-hydroxyl-4-chloro-1,2-benzisoxazole and 2-(N-tert-butoxycarbonylamino)ethanol The title compound was obtained in a yield of 63%.

Melting point: 110-111°C;

IR spectrum (KBr) v _max cm ^-1 : 3357, 1691, 1607, 1537;

NMR spectrum (DMSO-d ₆ ) δppm: 1.46 (9H, s), 3.66 (2H, q, J=5.1Hz),

4.51 (2H, t, J = 5.1Hz), 4.99 (1H, brs), 7.23 (1H, d, J = 7.6Hz), 7.34 (1H, d, J = 8.4Hz),

7.44 (1H, dd, J=8.4Hz, J=7.6Hz).(b) 3-(2-aminoethoxy)-4-chloro-1,2-benzisoxazole hydrochloride

React and work up in a similar manner to that described in Example 17(c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-chloro-1,2-benzisoxazole The title compound was obtained in 99% yield.

Melting point: 221-226°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3440, 3070, 3006, 2969, 2898, 1610, 1538,

1515;

NMR spectrum (DMSO-d ₆ ) δppm: 3.35 (2H, t, J = 5.1 Hz), 4.65 (2H, t, J = 5.4 Hz),

7.42-7.49 (1H, m), 7.62-7.71 (2H, m), 8.23 (3H, brs). Example 72 3-(2-aminoethoxy)-6-methylpyrido[3,2-d]isoxazole hydrochloride (a) ethyl 2-chloro-6-methylnicotinate

The title compound was prepared from 2-chloro-6-methylnicotinic acid by reacting and working up in a manner similar to that described in Example 1(a).

NMR spectrum (CDCl ₃ ) δppm: 1.41 (3H, t, J=7.2Hz), 2.59 (3H, s),

4.41 (2H, q, J = 7.2Hz), 7.16 (1H, d, J = 7.2Hz), 8.08 (1H, d, J = 7.2HZ). (b) 2-Chloro-6-methylpyridine-3-carboxyxamic acid

The title compound was prepared from ethyl 2-chloro-6-methylnicotinate by reacting and working up in a manner similar to that described in Example 10(b).

NMR spectrum (DMSO-d ₆ ) δppm: 2.51 (3H, s), 7.33 (1H, d, J=7.8Hz),

7.75 (1H, d, J = 7.8 Hz). (c) 3-Hydroxy-6-methylpyrido[3,2-d]isoxazole

The title compound was prepared from 2-chloro-6-methylpyridine-3-carboxyxamic acid by reacting and working up in a manner similar to that described in Example 10(c).

IR spectrum (KBr) v _max cm ^-1 : 2985, 2907, 2739, 2559, 1663, 1610, 1595,

1561, 1541;

NMR spectrum (DMSO-d ₆ ) δppm: 2.60 (3H, s), 7.30 (1H, d, J=8.0Hz),

8.14 (1H, d, J = 8.0 Hz). (d) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-6-methylpyrido[3,2-d]isoxazole

React and handle according to the similar method described in Example 1 (e), from 3-hydroxyl-6-methylpyrido[3,2-d]isoxazole and 2-(N-tert-butoxycarbonylamino)ethanol The title compound was obtained in 71% yield.

Melting point: 151-152°C;

IR spectrum (KBr) v _max cm ^-1 : 3332, 1718, 1708, 1614, 1609, 1534;

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 2.69 (3H, s),

3.64 (2H, q, J = 5.1Hz), 4.51 (2H, t, J = 5.1Hz), 4.94 (1H, brs), 7.15 (1H, d, J = 8.0Hz),

7.90 (1H, d, J=8.0Hz). (e) 3-(2-aminoethoxy)-6-methylpyrido[3,2-d]isoxazole hydrochloride

According to the similar reaction and treatment described in Example 1 (f), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-6-methylpyrido[3,2-d]iso Oxazole afforded the title compound in 97% yield.

Melting point: 209-213°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3426, 3063, 3000, 2938, 1669, 1609, 1565,

1536, 1506;

NMR spectrum (DMSO-d ₆ ) δppm: 2.63 (3H, s), 3.30-3.40 (2H, m),

4.62 (2H, t, J=5.1Hz), 7.40 (1Hd, J=8.0Hz), 8.18 (1H, d, J=8.0Hz), 8.29 (3H, brs). Example 733-(2-aminoethyl Oxy)-5-chloro-4-methyl-1,2-benzisoxazole hydrochloride and 3-(2-aminoethoxy)-5-chloro-7-methyl-1,2- Benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloro-4-methyl-1,2-benzisoxazole and 3 -(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloro-7-methyl-1,2-benzisoxazole

React and work up in a manner similar to that described in Example 17(b), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloro-1,2-benzisoxazole 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloro-4-methyl-1,2-benzisoxazole was obtained in a yield of 40%, and 3-(2 -(N-tert-butoxycarbonylamino)ethoxy)-5-chloro-7-methyl-1,2-benzisoxazole, yield 37%.

Data on 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloro-4-methyl-1,2-benzisoxazole.

Melting point: 140-141°C;

IR spectrum (KBr) v _max cm ^-1 : 3351, 1688, 1615, 1601, 1537;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 2.62 (3H, s),

3.66 (2H, q, J = 5.1Hz), 4.50 (2H, t, J = 5.1Hz), 4.88 (1H, brs), 7.19 (1H, d, J = 8.8Hz),

8.83(1H, d, J=8.8Hz).

Data on 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloro-7-methyl-1,2-benzisoxazole.

Melting point: 94-95°C;

IR spectrum (KBr) v _max cm ^-1 : 3333, 1686, 1611, 1539;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 2.48 (3H, s),

3.63 (2H, q, J = 5.1Hz), 4.49 (2H, t, J = 5.1Hz), 4.94 (1H, brs), 7.29 (1H, d, J = 1.8Hz),

7.44 (1H, d, J=1.8Hz). (b) 3-(2-aminoethoxy)-5-chloro-4-methyl-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloro-4-methyl-1,2-benzene and isoxazole to obtain the title compound in 99% yield.

Melting point: 223-226°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3451, 3009, 2970, 1645, 1618, 1605, 1536;

NMR spectrum (DMSO-d ₆ ) δppm: 2.62 (3H, s), 3.34 (2H, t, J=5.1Hz),

4.63(2H, t, J=5.1Hz), 7.52(1H, d, J=8.9Hz), 7.68(1H, d, J=8.9Hz), 8.28(3H, brs).(c)3-(2 -aminoethoxy)-5-chloro-7-methyl-1,2-benzisoxazole hydrochloride

According to the similar reaction and treatment described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-chloro-7-methyl-1,2-benzene and isoxazole to obtain the title compound in 98% yield.

Melting point: 208-211°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3428, 3056, 2966, 2894, 2770, 1608, 1541,

1517;

NMR spectrum (DMSO-d ₆ ) δppm: 2.46 (3H, s), 3.34 (2H, t, J=5.1Hz),

460(2H, t, J=51Hz), 7.59(1H, d, J=18Hz), 7.69(1H, d, J=1.8Hz), 8.32(3H, brs). Embodiment 743-(2 -aminoethoxy)-5-bromo-4-methyl-1,2-benzisoxazole hydrochloride and 3-(2-aminoethoxy)-5-bromo-7-methyl-1 , 2-Benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-bromo-4-methyl-1,2-benzoisox Azole and 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-bromo-7-methyl-1,2-benzisoxazole

React and work up in a similar manner to that described in Example 17(b), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-bromo-1,2-benzisoxazole 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-bromo-4-methyl-1,2-benzisoxazole was obtained in a yield of 7%, and 3-(2 -(N-tert-butoxycarbonylamino)ethoxy)-5-bromo-7-methyl-1,2-benzisoxazole, yield 68%.

Data on 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-bromo-4-methyl-1,2-benzisoxazole.

Melting point: 140-141°C;

IR spectrum (KBr) v _max cm ^-1 : 3350, 1688, 1618, 1595, 1538;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 2.64 (3H, s),

3.66 (2H, q, J = 5.1Hz), 4.50 (2H, t, J = 5.1Hz), 4.88 (1H, brs), 7.14 (1H, d, J = 8.8Hz),

7.63(1H, d, J=8.8Hz).

Data on 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-bromo-7-methyl-1,2-benzisoxazole.

Melting point: 79-80°C;

IR spectrum (KBr) v _max cm ^-1 : 3350, 1692, 1612, 1535;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 2.48 (3H, s),

3.65 (2H, q, J = 5.1Hz), 4.49 (2H, t, J = 5.1Hz), 4.95 (1H, brs), 7.29 (1H, d, J = 1.8Hz),

7.44 (1H, d, J=1.8Hz). (b) 3-(2-aminoethoxy)-5-bromo-4-methyl-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-bromo-4-methyl-1,2-benzene and isoxazole to obtain the title compound in 96% yield.

Melting point: 208-212°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3436, 3000, 1615, 1599, 1535;

NMR spectrum (DMSO-d ₆ ) δppm: 2.64 (3H, s), 3.34 (2H, t, J=5.1Hz),

4.63 (2H, t, J = 5.1Hz), 7.46 (1H, d, J = 8.9Hz), 7.82 (1H, d, J = 8.9Hz), 8.24 (3H, brs). (c) 3-(2 -aminoethoxy)-5-bromo-7-methyl-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-bromo-7-methyl-1,2-benzene and isoxazole to obtain the title compound in 98% yield.

Melting point: 212-215°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3339, 3054, 2968, 2925, 2892, 1606, 1546,

1516;

NMR spectrum (DMSO-d ₆ ) δppm: 2.46 (3H, s), 3.33 (2H, t, J=5.1Hz),

4.60 (2H, t, J=5.1Hz), 7.70 (1H, d, J=1.8Hz), 7.82 (1H, d, J=1.8Hz), 8.28 (3H, brs). Embodiment 753-(2- Aminoethoxy)-4,5-dimethyl-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4, 5-Dimethyl-1,2-benzoisoxazole

Reaction and treatment according to the similar method described in Example 51 (a), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-methyl-1,2-benzisoxazole The title compound was obtained in 73% yield.

Melting point: 125-126°C;

IR spectrum (KBr) v _max cm ^-1 : 3352, 1694, 1678, 1620, 1609, 1539;

NMR spectrum (CDCl ₃ ) δppm: 1-46 (9H, s), 2.33 (3H, s), 2.51 (3H, s),

3.65(2H, q, J=5.1Hz), 4.49(2H, t, J=5.1Hz), 4.90(1H, brs), 7.13(1H, d, J=8.5Hz),

7.29 (1H, d.J=8.5Hz).(b) 3-(2-aminoethoxy)-4,5-dimethyl-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4,5-dimethyl-1,2-benzo Isoxazole afforded the title compound in 96% yield.

Melting point: 180-183°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3434, 2971, 2924, 2751, 1643, 1612, 1538;

NMR spectrum (DMSO-d ₆ ) δppm: 2.32 (3H, s), 2.51 (3H, s),

3.34 (2H, t, J = 5.1Hz), 4.61 (2H, t, J = 5.1Hz), 7.31 (1H, d, J = 8.5Hz),

7 43 (1H, d, J=8.5Hz), 8.28 (3H, brs). Example 76 3-(2-aminoethoxy)-4-methyl-5-methoxy-1,2-benzo Isoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-methyl-5-methoxy-1,2-benzisoxazole

According to the reaction and treatment similar to that described in Example 51(a), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-methoxy-1,2-benzoisoxane Azole was used to obtain the title compound in 88% yield.

Melting point: 137-138°C;

IR spectrum (KBr) v _max cm ^-1 : 3361, 1689, 1618, 1538;

NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 2.46 (3H, s),

3.65(2H, q, J=5.1Hz), 3.87(3H, s), 4.48(2H, t, J=5.1Hz), 4.90(1H, brs),

7.12 (1H, d, J = 8.9 Hz), 7.18 (1 H, d, J = 8.9 Hz). (b) 3-(2-aminoethoxy)-4-methyl-5-methoxy-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-methyl-5-methoxy-1,2 - Benzisoxazole The title compound was obtained in 99% yield.

Melting point: 173-176°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3423, 3008, 2971, 2920, 2842, 1617, 1601,

1536, 1500;

NMR spectrum (DMSO-d ₆ ) δppm: 244 (3H, s), 3.35 (2H, t, J=5.1Hz),

3.84(3H, s), 4.60(2H, t, J=5.1Hz), 7.35(1H, d, J=9.0Hz), 7.40(1H, d, J=9.0Hz),

8.32(3H, brs). Example 77 3-(2-aminoethoxy)-5-carbamoyl-1,2-benzisoxazole hydrochloride (a) 3-(2-(N-tert Butoxycarbonylamino)ethoxy)-5-carbamoyl-1,2-benzisoxazole

React and work up in a similar manner to that described in Example 23(a), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-bromo-1,2-benzisoxazole The title compound was obtained in 12% yield.

Melting point: 178-180°C;

IR spectrum (KBr) v _max cm ^-1 : 3348, 3197, 1717, 1672, 1624, 1599, 1543;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.65 (2H, q, J=5.1Hz),

4.53(2H, t, J=5.1Hz), 5.00(1H, brs), 5.50-6.50(2H, brs), 7.49(1H, d, J=8.8Hz),

8.04(1H, d, J=8.8Hz), 8.16(1H, s).(b) 3-(2-aminoethoxy)-5-carbamoyl-1,2-benzisoxazole hydrochloride Salt

According to the reaction and treatment similar to that described in Example 17(c), 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-carbamoyl-1,2-benzoisoxane Azole was used to obtain the title compound in 96% yield.

Melting point: 218-222°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3429, 3353, 3317, 3195, 2977, 2901, 1671,

1622, 1596, 1546, 1501;

NMR spectrum (DMSO-d ₆ ) δppm: 3.33 (2H, t, J = 5.1 Hz),

4.64(2H, t, J=5.1Hz), 7.51(1H, s), 7.72(1H, d, J=8.8Hz), 8.18(1H, s),

8.21 (1H, d, J=8.8Hz), 8.3 1 (3H, brs), 8.40 (1H, s). Example 783-(2-aminoethoxy)-5-cyano-1,2-benzene Isoxazole hydrochloride (a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-cyano-1,2-benzisoxazole

According to the reaction and treatment similar to that described in Example 24 (a), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-carbamoyl-1,2-benzoisoxane Azole was used to obtain the title compound in 92% yield.

Melting point: 138-140°C;

IR spectrum (KBr) v _max cm ^-1 : 3349, 2233, 1717, 1708, 1623, 1605, 1540,

1527;

NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 3.65 (2H, q, J=5.1Hz),

4.53(2H,t,J=5.1Hz), 4.93(1H,brs), 7.56(1H,d,J=8.8Hz), 7.79(1H,d,J=8.8Hz),

8.04(1H,s).(b) 3-(2-aminoethoxy)-5-cyano-1,2-benzisoxazole hydrochloride

Reaction and treatment according to the similar method described in Example 17 (c), from 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-cyano-1,2-benzisoxazole The title compound was obtained in 96% yield.

Melting point: 212-216°C (decomposition);

IR spectrum (KBr) v _max cm ^-1 : 3171, 3096, 3058, 3029, 2953, 2239, 1624,

1601, 1544, 1518;

NMR spectrum (DMSO-d ₆ ) δppm: 3.34 (2H, t, J = 5.1 Hz), 4.65 (2H, t, J = 5.1 Hz),

7.91 (1H, d, J = 8.8Hz), 8.12 (1H, d, J = 8.8Hz), 8.35 (3H, brs), 8.43 (1H, s). Test Method 1 Monoamine Oxidase Inhibitory Activity

The assay was carried out according to the methods described in Biochem. Pharmacol., 12, 1439 (1963) and J. Neurochem., 35, 109 (1980). 210 μl of phosphate buffer (pH 7.4) and 30 μl of test compound (dissolved in 10% DMSO-water) were added to 30 μl of crude mitochondrial sample of mouse brain (30 μg protein), and the mixture was pre-incubated at 38°C for 20 minutes . Thereafter, 14C-2-phenylethylamine (PEA, final concentration: 20 μM) was added to determine the B-type monoamine oxidase inhibitory activity; and 14C-5-hydroxytryptamine (5-HT, final concentration: 100 μM) was added to determine A- Type monoamine oxidase inhibitory activity, the mixture was reacted at 38 ° C for 20 minutes. After the reaction was completed, the reactant was suspended by adding 2N-HCl (200 μl), and the 14C-labeled metabolite produced by the reaction was extracted with a solvent (ethyl acetate:toluene=1:1), and the 14C was measured with a liquid scintillation counter. to determine the compound concentration (IC ₅₀ ) that caused a 50% decrease in the 14C radioactivity of the control group. The results are shown in Table 17.

Table 17. Monoamine oxidase inhibitory activity

Example No. B-Type Monoamine Oxidase Inhibitory Activity (IC ₅₀ )

1 ^*) 0.37nM

2 1.85nM

5 ^*) 1.35nM

6 ^*) 5.60nM

7 ^*) 0.56nM

8 ^*) 0.56nM

9 20.0nM

10(e) 10.2nM

10(f) 13.5nM

11 2.8nM

12 26.5nM

13 27.5nM

14 21.5nM

15 ^*) 0.32nM

17 4.2nM

21 4.7nM

24 6.8nM

26 2.7nM

33 4.5nM

34 2.2nM

35 9.0nM

38 2.95nM

42 18.0nM

44 6.0nM

56 6.6nM Compound A ^**) 2.35μM Compound B ^***) 4.70μM Note: ^* ) indicates that the inhibitory activity of B-type monoamine oxidase is 4500-55000 times that of A-type monoamine oxidase. ^** ) 3-(2-N-Methylamino)ethoxy-1,2-benzisoxazole. ^*** ) 3-(2-N,N'-dimethylamino)ethoxy-1,2-benzisoxazole. Formulation Example 1 Hard Capsules

Single-dose capsules were prepared by filling each standard hard gelatin capsule with 100 mg of the powdered compound described in Example 1, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate, and the prepared single-dose capsules were washed And dry to obtain hard capsules.

[industrial applicability]

The isoxazole derivatives (I) and (II) of the present invention have significant B-type monoamine oxidase inhibitory activity and A-type monoamine oxidase inhibitory activity (especially have strong inhibitory effect on B-type monoamine oxidase) and have a lower Therefore, they are useful as therapeutic or preventive agents for neurological diseases such as Parkinson's disease, depression, Alzheimer's disease, etc. (particularly Parkinson's disease).

When the compounds (I) and (II) of the present invention or pharmaceutically acceptable salts thereof are used as therapeutic or preventive agents for the above-mentioned neuropathy, the compounds may be used by themselves or with suitable pharmaceutically acceptable excipients. Oral administration in the form of tablets, capsules, granules, powders, syrups, etc., or parenteral administration through injection or suppositories.

These preparations can be prepared by conventional methods using additives such as excipients (such as sugar derivatives such as lactose, sucrose, fructose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, α- Starches, dextrins, and carboxymethyl starches; cellulose derivatives such as microcrystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carmellose, calcium carboxyformate, and internal cross Carmellose sodium; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate and aluminum magnesium silicate; phosphates such as calcium phosphate ; carbonates such as calcium carbonate; sulfates such as calcium sulfate, etc.), binders (such as the above-mentioned excipients; gelatin; polyvinylpyrrolidone; polyethylene glycol, etc.), decay agents (such as the above-mentioned excipients; crosslinking Carboxymethyl ether cellulose sodium, carboxymethyl starch sodium, chemically modified starch such as cross-linked polyvinylpyrrolidone, cellulose derivatives, etc.), lubricants (such as talc; stearic acid; metal stearate such as Calcium and magnesium stearates; silica gels; shellacs such as propolis and spermaceti; boric acids; glycols; carboxylic acids such as fumaric and adipic acids; sodium carboxylates such as sodium benzoate; sulfates such as sodium sulfate; acid; lauryl sulfate such as sodium lauryl sulfate, magnesium lauryl sulfate; silicic acid such as silicic anhydride and silicic acid hydrate; starch derivatives mentioned in the above-mentioned excipients), pesticides (such as parabens such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethylene glycol; benzalkonium chloride; phenols such as phenol and cresol ; sodium ethylmercury thiosalicylate; acetic anhydride; sorbic acid, etc.), flavoring agents or flavor enhancers (such as commonly used sweeteners, sour agents, fragrances, etc.), diluents and solvents for injection (such as water, ethanol and glycerin, etc.). The dose used may vary depending on symptoms, age, etc., but preferably, in the case of oral administration, the minimum amount is 1 mg (preferably 10 mg) and the maximum amount is 2000 mg (preferably 400 mg) per day for adults, and intravenously In the case of administration, the minimum dose per day is 0.1 mg (preferably 1 mg) and the maximum dose is 500 mg (preferably 300 mg), and depending on the symptoms, it can be administered 1-6 times per day.

Claims (61)

1. The compound of the following formula (I) or a pharmaceutically acceptable salt thereof Wherein R ¹ represents a hydrogen atom; a halogen atom; C ₁ -C ₆ alkyl; a C ₁ -C ₄ alkyl substituted by halogen- or C ₁ -C ₄ alkoxy; C ₁ -C ₆ alkoxy; Halogenated C ₁ -C ₆ alkoxy; Hydroxy; C ₁ -C ₆ Alkylthio; Amino; Mono C ₁ -C ₆ Alkylamino; Di C ₁ -C ₆ Alkylamino; C ₁ -C ₆ Chain Alkanoyl; C ₁ -C ₆ alkanoylamino; C ₁ -C ₆ alkanoyloxy; C ₁ -C ₆ alkoxycarbonyl; carboxyl; (C ₁ -C ₆ alkylthio)thiocarbonyl; amino Formyl; single C ₁ -C ₆ alkylcarbamoyl; two C ₁ -C ₆ alkylcarbamoyl; nitro or cyano group, R ² represents an amino group, m represents an integer of 1-3, n represents an integer of 1-6, and ring A represents a benzene ring fused to an isoxazole ring, a naphthalene ring fused to an isoxazole ring, or a ring fused to an isoxazole ring containing 1 or 2 oxygen atoms selected from , a 5- or 6-membered heteroaromatic ring of a nitrogen atom and a sulfur atom heteroatom, and X represents an oxygen atom or a sulfur atom, provided that, when m is an integer of 2 or 3, each of the substituents R ^is the same or different. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ^R represents a hydrogen atom, a halogen atom, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2 -Fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, fluoromethoxy, chloromethyl Oxygen, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2, 2,2-trifluoroethoxy, hydroxyl, C ₁ -C ₄ alkylthio, amino, mono C ₁ -C ₄ alkylamino, di C ₁ -C ₄ alkylamino, formyl, acetyl, formyl Amylamino, Acetylamino, C ₁ -C ₄ Alkanoyloxy, C ₁ -C ₄ Alkoxycarbonyl, Carboxyl, (Methylthio)thiocarbonyl, (Ethylthio)thiocarbonyl, Carbamoyl, A methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, nitro or cyano group. 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ^R represents a hydrogen atom, a halogen atom, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2 -Fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, difluoromethoxy, hydroxyl, C ₁ -C ₄ Alkylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, formyl, acetyl, formylamino, acetamido, C ₁ -C ₄ alkoxycarbonyl, carboxyl, carbamoyl, methyl Carbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, nitro or cyano groups. 4. The compound or pharmaceutically acceptable salt thereof according to claim ¹ , wherein R represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, trifluoromethyl, methoxy, ethoxy Difluoromethoxy, hydroxyl, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, formyloxy, acetoxy, methoxycarbonyl, ethoxycarbonyl, carboxyl, amino Formyl, nitro or cyano groups. 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R represents a hydrogen atom, a fluorine atom, a chlorine atom, ^a bromine atom, a methyl group, a methoxy group, a methylthio group, a difluoromethoxy group, Methoxycarbonyl, nitro or cyano groups. 6. A compound according to any one of claims 1-5, wherein m is 2, or a pharmaceutically acceptable salt thereof. 7. A compound according to any one of claims 1-5, wherein m is 1, or a pharmaceutically acceptable salt thereof. 8. A compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein n is 2-4. 9. A compound according to any one of claims 1-7, wherein n is 2, or a pharmaceutically acceptable salt thereof. 10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein ring A is phenyl, naphthyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, Thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl rings. 11. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein Ring A is a phenyl, naphthyl or pyridyl ring. 12. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein Ring A is a phenyl or pyridyl ring. 13. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein Ring A is a phenyl ring. 14. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom. 15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of 3-(2-Aminoethoxy)benzisoxazole, 3-(2-Aminoethylthio)benzisoxazole, 3-(2-Aminoethoxy)-fluorobenzoisoxazole, 3-(2-Aminoethylthio)-fluorobenzisoxazole, 3-(2-Aminoethoxy)-fluoro-methylbenzisoxazole, 3-(2-Aminoethylthio)-fluoro-methylbenzisoxazole, 3-(2-Aminoethoxy)-fluoro-methylthiobenzisoxazole, 3-(2-Aminoethoxy)-fluoro-methoxycarbonylbenzisoxazole, 3-(2-Aminoethoxy)-fluoro-carbamoylbenzisoxazole, 3-(2-Aminoethoxy)-fluoro-cyanobenzisoxazole, 3-(2-Aminoethylthio)-fluoro-cyanobenzisoxazole, 3-(2-Aminoethoxy)-chlorobenzisoxazole, 3-(2-Aminoethylthio)-chlorobenzisoxazole, 3-(2-Aminoethoxy)-dichlorobenzisoxazole, 3-(2-Aminoethylthio)-dichlorobenzisoxazole, 3-(2-Aminoethoxy)-chloro-methylbenzisoxazole, 3-(2-Aminoethylthio)-chloro-methylbenzisoxazole, 3-(2-Aminoethoxy)-chloro-carbamoylbenzisoxazole, 3-(2-Aminoethoxy)-chloro-cyanobenzisoxazole, 3-(2-Aminoethylthio)-chloro-cyanobenzisoxazole, 3-(2-Aminoethoxy)-dichloro-methylbenzisoxazole, 3-(2-Aminoethoxy)-bromobenzisoxazole, 3-(2-Aminoethoxy)-bromo-methylbenzisoxazole, 3-(2-Aminoethoxy)-methylbenzisoxazole, 3-(2-Aminoethylthio)-methylbenzisoxazole, 3-(2-Aminoethoxy)-dimethylbenzisoxazole, 3-(2-Aminoethoxy)-methyl-methoxybenzisoxazole, 3-(2-Aminoethoxy)-methyl-methylthiobenzisoxazole, 3-(2-Aminoethoxy)-methyl-methoxycarbonylbenzisoxazole, 3-(2-Aminoethoxy)-methyl-carbamoylbenzoisoxazole, 3-(2-Aminoethoxy)-methyl-cyanobenzisoxazole, 3-(2-Aminoethoxy)-trifluoromethylbenzisoxazole, 3-(2-Aminoethoxy)-methoxybenzisoxazole, 3-(2-Aminoethylthio)-methoxybenzisoxazole, 3-(2-Aminoethoxy)-difluoromethoxybenzisoxazole, 3-(2-Aminoethoxy)-hydroxybenzoisoxazole, 3-(2-Aminoethoxy)-aminobenzisoxazole, 3-(2-Aminoethylthio)-aminobenzisoxazole, 3-(2-Aminoethoxy)-methylaminobenzisoxazole, 3-(2-Aminoethoxy)-dimethylaminobenzisoxazole, 3-(2-Aminoethoxy)-acetoxybenzisoxazole, 3-(2-Aminoethoxy)-carboxybenzisoxazole, 3-(2-Aminoethoxy)-methoxycarbonylbenzisoxazole, 3-(2-Aminoethoxy)-carbamoylbenzisoxazole, 3-(2-Aminoethoxy)-nitrobenzisoxazole, 3-(2-Aminoethylthio)-nitrobenzisoxazole, 3-(2-Aminoethoxy)-cyanobenzisoxazole, 3-(2-Aminoethoxy)-naphthoisoxazole, 3-(2-Aminoethoxy)-pyridoisoxazole, 3-(2-Aminoethoxy)-chloropyridoisoxazole, 3-(2-Aminoethylthio)-chloropyridisoxazole, 3-(2-Aminoethoxy)-picolineisoxazole, or 3-(2-Aminoethoxy)-trifluoromethylpyridoisoxazole. 16. The compound according to claim 1, selected from 3-(2-aminoethoxy)-1,2-benzisoxazoles, and pharmaceutically acceptable salts thereof. 17. A compound according to claim 1 selected from 3-(2-aminoethoxy)-5-fluoro-1,2-benzisoxazoles and pharmaceutically acceptable salts thereof. 18. The compound according to claim 1, selected from the group consisting of 3-(2-aminoethoxy)-5-fluoro-4-methyl-1,2-benzoisoxane and pharmaceutically acceptable salts thereof azole. 19. A compound according to claim 1 selected from 3-(2-aminoethylthio)-5-fluoro-1,2-benzisoxazoles and pharmaceutically acceptable salts thereof. 20. A compound according to claim 1 selected from 3-(2-aminoethoxy)-5-chloro-1,2-benzisoxazoles and pharmaceutically acceptable salts thereof. 21. A compound according to claim 1 selected from 3-(2-aminoethoxy)-5,7-dichloro-1,2-benzisoxazole and pharmaceutically acceptable salts thereof. 22. The compound according to claim 1, selected from the group consisting of 3-(2-aminoethylthio)-5-chloro-7-methyl-1,2-benzoisoxane and pharmaceutically acceptable salts thereof azole. 23. The compound according to claim 1, selected from 3-(2-aminoethylthio)-5-chloro-1,2-benzisoxazole, and pharmaceutically acceptable salts thereof. 24. A compound according to claim 1 selected from 3-(2-aminoethoxy)-6-chloro-1,2-benzisoxazoles and pharmaceutically acceptable salts thereof. 25. The compound according to claim 1, selected from 3-(2-aminoethoxy)-7-chloro-1,2-benzisoxazole, and pharmaceutically acceptable salts thereof. 26. A compound according to claim 1 selected from 3-(2-aminoethoxy)-5-bromo-1,2-benzisoxazoles and pharmaceutically acceptable salts thereof. 27. The compound according to claim 1, selected from 3-(2-aminoethoxy)-5-methyl-1,2-benzisoxazole, and pharmaceutically acceptable salts thereof. 28. The compound according to claim 1, selected from 3-(2-aminoethylthio)-5-methyl-1,2-benzisoxazole, and pharmaceutically acceptable salts thereof. 29. The compound according to claim 1, selected from 3-(2-aminoethoxy)-6-methyl-1,2-benzisoxazole, and pharmaceutically acceptable salts thereof. 30. The compound according to claim 1, selected from 3-(2-aminoethoxy)-7-methyl-1,2-benzisoxazole, and pharmaceutically acceptable salts thereof. 31. A compound according to claim 1 selected from 3-(2-aminoethoxy)-5-methoxy-1,2-benzisoxazoles and pharmaceutically acceptable salts thereof. 32. The compound according to claim 1, selected from 3-(2-aminoethylthio)-5-methoxy-1,2-benzisoxazole, and pharmaceutically acceptable salts thereof. 33. The compound according to claim 1, selected from the group consisting of 3-(2-aminoethoxy)-5-difluoromethoxy-1,2-benzisoxazole, and pharmaceutically acceptable salts thereof . 34. The compound according to claim 1, selected from the group consisting of 3-(2-aminoethoxy)-5-fluoro-4-methylthio-1,2-benziso Oxazole. 35. A compound according to claim 1 selected from 3-(2-aminoethoxy)-5-methoxycarbonyl-1,2-benzisoxazoles and pharmaceutically acceptable salts thereof. 36. A compound according to claim 1 selected from 3-(2-aminoethoxy)-5-nitro-1,2-benzisoxazoles and pharmaceutically acceptable salts thereof. 37. The compound according to claim 1, selected from 3-(2-aminoethylthio)-5-nitro-1,2-benzisoxazole, and pharmaceutically acceptable salts thereof. 38. A compound according to claim 1 selected from 3-(2-aminoethoxy)-4-cyano-1,2-benzisoxazoles and pharmaceutically acceptable salts thereof. 39. A compound according to claim 1 selected from 3-(2-aminoethoxy)pyrido[3,2-d]isoxazoles and pharmaceutically acceptable salts thereof. 40. A monoamine oxidase inhibitor comprising, as an active ingredient, an isoxazole derivative of the following general formula or a pharmaceutically acceptable salt thereof:

wherein R ¹ represents a hydrogen atom; a halogen atom; C ₁ -C ₆ alkyl; C 1 -C ₄ alkyl substituted by halogen or C _{1 -C 4} alkoxy; C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; hydroxyl; C ₁ -C ₆ alkylthio; amino; mono C ₁ -C ₆ alkylamino; di C ₁ -C ₆ alkylamino; C ₁ -C ₆ alkanoyl ; C ₁ -C ₆ alkanoylamino; C ₁ -C ₆ alkanoyloxy; C ₁ -C ₆ alkoxycarbonyl; carboxyl; (C ₁ -C ₆ alkylthio)thiocarbonyl; carbamoyl ; mono C ₁ -C ₆ alkylcarbamoyl; di C ₁ -C ₆ alkylcarbamoyl; nitro or cyano group, R ² _a represents amino; mono C ₁ -C ₄ alkylamino; di C ₁ -C ₄ alkylamino; or a 5- or 6-membered heterocyclic group containing 1 nitrogen atom and optionally another nitrogen or oxygen atom, provided that the group is attached via the nitrogen atom; m represents an integer of 1-3, n represents an integer of 1-6, ring A represents a benzene ring fused to an isoxazole ring, a naphthalene ring fused to an isoxazole ring or a ring fused to an isoxazole ring containing 1 or 2 5- or 6-membered heteroaromatic rings selected from oxygen atoms, nitrogen atoms, and sulfur atom heteroatoms, and X represents an oxygen atom or a sulfur atom, provided that, when m is an integer of 2 or 3, all The substituents R ¹ are the same or different. 41. The monoamine oxidase inhibitor according to claim 40, which contains as an active ingredient an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein ^R represents a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, fluorine Methyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, fluoromethoxy, chloromethoxy, trifluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 1-fluoroethoxy, 2- Fluoroethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, hydroxyl, C ₁ -C ₄ alkylthio, amino, mono C ₁ -C ₄ alkylamino, di-C ₁ -C ₄ alkylamino, formyl, acetyl, formylamino, acetylamino, C ₁ -C ₄ alkanoyloxy, C ₁ -C ₄ alkoxycarbonyl, carboxyl, (methylthio)thiocarbonyl , (ethylthio)thiocarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, nitro or cyano groups. 42. The monoamine oxidase inhibitor according to claim 40, which contains as an active ingredient an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein ^R represents a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, fluorine Methyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy , difluoromethoxy, hydroxyl, C ₁ -C ₄ alkylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, formyl, acetyl, formylamino, acetamido, C ₁ - C ₄ alkoxycarbonyl, carboxy, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, nitro or cyano groups. 43. The monoamine oxidase inhibitor according to claim 40, which contains as an active ingredient an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein ^R represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, Ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, hydroxyl, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, formyloxy, acetyl Oxy, methoxycarbonyl, ethoxycarbonyl, carboxy, carbamoyl, nitro or cyano groups. 44. The monoamine oxidase inhibitor according to claim 40, which contains as an active ingredient an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein ^R represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, Methoxy, methylthio, difluoromethoxy, methoxycarbonyl, nitro or cyano groups. 45. The monoamine oxidase inhibitor according to any one of claims 40-44, which contains as an active ingredient an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein R ² _a represents amino, methylamino, dimethyl Amino, piperidinyl or morpholinyl groups. 46. The monoamine oxidase inhibitor according to any one of claims 40-44, which contains as an active ingredient an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein R ² _a represents amino, piperidinyl or hydrazine Linyl group. 47. The monoamine oxidase inhibitor according to any one of claims 40 to 44, which contains as an active ingredient an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein ^R2a represents _an amino group. 48. The monoamine oxidase inhibitor according to any one of claims 40-47, which contains an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein m is 2, as an active ingredient. 49. The monoamine oxidase inhibitor according to any one of claims 40-47, which contains an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein m is 1, as an active ingredient. 50. The monoamine oxidase inhibitor according to any one of claims 40-49, which contains an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein n is 2-4, as an active ingredient. 51. The monoamine oxidase inhibitor according to any one of claims 40-49, which contains an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein n is 2, as an active ingredient. 52. The monoamine oxidase inhibitor according to any one of claims 40-51, which contains as an active ingredient an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, naphthyl, furyl , thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl rings. 53. The monoamine oxidase inhibitor according to any one of claims 40-51, which contains as an active ingredient an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, naphthyl or pyridyl ring. 54. The monoamine oxidase inhibitor according to any one of claims 40 to 51, which contains as an active ingredient an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl or pyridyl ring. 55. The monoamine oxidase inhibitor according to any one of claims 40 to 51, which contains as an active ingredient an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl ring. 56. The monoamine oxidase inhibitor according to any one of claims 40 to 55, which contains as an active ingredient an isoxazole derivative or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom. 57. The monoamine oxidase inhibitor according to claim 40, which is selected from the group consisting of 3-(2-Aminoethoxy)benzisoxazole, 3-(2-Aminoethylthio)benzisoxazole, 3-(2-Aminoethoxy)-fluorobenzoisoxazole, 3-(2-Aminoethylthio)-fluorobenzisoxazole, 3-(2-Aminoethoxy)-fluoro-methylbenzisoxazole, 3-(2-Aminoethylthio)-fluoro-methylbenzisoxazole, 3-(2-Aminoethoxy)-fluoro-methylthiobenzisoxazole, 3-(2-Aminoethoxy)-fluoro-methoxycarbonylbenzisoxazole, 3-(2-Aminoethoxy)-fluoro-carbamoylbenzisoxazole, 3-(2-Aminoethoxy)-fluoro-cyanobenzisoxazole, 3-(2-Aminoethylthio)-fluoro-cyanobenzisoxazole, 3-(2-Aminoethoxy)-chlorobenzisoxazole, 3-(2-Aminoethylthio)-chlorobenzisoxazole, 3-(2-Aminoethoxy)-dichlorobenzisoxazole, 3-(2-Aminoethylthio)-dichlorobenzisoxazole, 3-(2-Aminoethoxy)-chloro-methylbenzisoxazole, 3-(2-Aminoethylthio)-chloro-methylbenzisoxazole, 3-(2-Aminoethoxy)-chloro-carbamoylbenzisoxazole, 3-(2-Aminoethoxy)-chloro-cyanobenzisoxazole, 3-(2-Aminoethylthio)-chloro-cyanobenzisoxazole, 3-(2-Aminoethoxy)-dichloro-methylbenzisoxazole, 3-(2-Aminoethoxy)-bromobenzisoxazole, 3-(2-Aminoethoxy)-bromo-methylbenzisoxazole, 3-(2-Aminoethoxy)-methylbenzisoxazole, 3-(2-Aminoethylthio)-methylbenzisoxazole, 3-(2-Aminoethoxy)-dimethylbenzisoxazole, 3-(2-Aminoethoxy)-methyl-methoxybenzisoxazole, 3-(2-Aminoethoxy)-methyl-methylthiobenzisoxazole, 3-(2-Aminoethoxy)-methyl-methoxycarbonylbenzisoxazole, 3-(2-Aminoethoxy)-methyl-carbamoylbenzoisoxazole, 3-(2-Aminoethoxy)-methyl-cyanobenzisoxazole, 3-(2-Aminoethoxy)-trifluoromethylbenzisoxazole, 3-(2-Aminoethoxy)-methoxybenzisoxazole, 3-(2-Aminoethylthio)-methoxybenzisoxazole, 3-(2-Aminoethoxy)-difluoromethoxybenzisoxazole, 3-(2-Aminoethoxy)-hydroxybenzoisoxazole, 3-(2-Aminoethoxy)-aminobenzisoxazole, 3-(2-Aminoethylthio)-aminobenzisoxazole, 3-(2-Aminoethoxy)-methylaminobenzisoxazole, 3-(2-Aminoethoxy)-dimethylaminobenzisoxazole, 3-(2-Aminoethoxy)-acetoxybenzisoxazole, 3-(2-Aminoethoxy)-carboxybenzisoxazole, 3-(2-Aminoethoxy)-methoxycarbonylbenzisoxazole, 3-(2-Aminoethoxy)-carbamoylbenzisoxazole, 3-(2-Aminoethoxy)-nitrobenzisoxazole, 3-(2-Aminoethylthio)-nitrobenzisoxazole, 3-(2-Aminoethoxy)-cyanobenzisoxazole, 3-(2-Aminoethoxy)-naphthoisoxazole, 3-(2-Aminoethoxy)-pyridoisoxazole, 3-(2-Aminoethoxy)-chloropyridoisoxazole, 3-(2-Aminoethylthio)-chloropyridisoxazole, 3-(2-Aminoethoxy)-picolineisoxazole, or 3-(2-Aminoethoxy)-trifluoromethylpyridoisoxazole and pharmaceutically acceptable salts thereof. 58. The monoamine oxidase inhibitor according to claim 40, which is selected from the group consisting of: 3-(2-aminoethoxy)-1,2-benzisoxazole, 3-(2-aminoethoxy)-5-fluoro-1,2-benzisoxazole, 3-(2-Aminoethoxy)-5-fluoro-4-methyl-1-di-benzisoxazole, 3-(2-Aminoethylthio)-5-fluoro-1,2-benzisoxazole, 3-(2-aminoethoxy)-5-chloro-1,2-benzisoxazole, 3-(2-Aminoethoxy)-5,7-dichloro-1,2-benzisoxazole, 3-(2-Aminoethylthio)-5-chloro-7-methyl-1,2-benzisoxazole, 3-(2-Aminoethylthio)-5-chloro-1,2-benzisoxazole, 3-(2-Aminoethoxy)-6-chloro-1,2-benzisoxazole, 3-(2-Aminoethoxy)-7-chloro-1,2-benzisoxazole, 3-(2-aminoethoxy)-5-bromo-1,2-benzisoxazole, 3-(2-aminoethoxy)-5-methyl-1,2-benzisoxazole, 3-(2-Aminoethylthio)-5-methyl-1,2-benzisoxazole, 3-(2-aminoethoxy)-6-methyl-1,2-benzisoxazole, 3-(2-aminoethoxy)-7-methyl-1,2-benzisoxazole, 3-(2-aminoethoxy)-5-methoxy-1,2-benzisoxazole, 3-(2-Aminoethylthio)-5-methoxy-1,2-benzisoxazole, 3-(2-aminoethoxy)-5-difluoromethoxy-1,2-benzisoxazole, 3-(2-Aminoethoxy)-5-fluoro-4-methylthio-1,2-benzisoxazole, 3-(2-Aminoethoxy)-5-methoxycarbonyl-1,2-benzisoxazole, 3-(2-aminoethoxy)-5-nitro-1,2-benzisoxazole, 3-(2-Aminoethylthio)-5-nitro-1,2-benzisoxazole, 3-(2-Aminoethoxy)-4-cyano-1,2-benzisoxazole, or 3-(2-Aminoethoxy)pyrido[3,2-d]isoxazole and pharmaceutically acceptable salts thereof. 59. The preparation method of the compound of formula (I) described in claim 1 or a pharmaceutically acceptable salt thereof, the method comprising: (1) reacting the compound of the following general formula (XV) with a halogenating agent to obtain the following general formula ( Halogenated-isoxazole derivatives of XVI), wherein R ¹ represents a hydrogen atom; a halogen atom; C ₁ -C ₆ alkyl; C 1 -C ₄ alkyl substituted by halogen or C _{1 -C 4} alkoxy; C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; hydroxyl; C ₁ -C ₆ alkylthio; amino; mono C ₁ -C ₆ alkylamino; di C ₁ -C ₆ alkylamino; C ₁ -C ₆ alkanoyl ; C ₁ -C ₆ alkanoylamino; C ₁ -C ₆ alkanoyloxy; C ₁ -C ₆ alkoxycarbonyl; carboxyl; (C ₁ -C ₆ alkylthio)thiocarbonyl; carbamoyl ; mono-C ₁ -C ₆ alkylcarbamoyl; di-C ₁ -C ₆ alkylcarbamoyl; nitro or cyano groups, m represents an integer of 1-3, A represents a benzene ring fused to an isoxazole ring, a naphthalene ring fused to an isoxazole ring or a heteroatom containing 1 or 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom 5- or 6-membered aromatic heterocycle, wherein R ¹ , m and A are as described above, Z represents a halogen atom, and the compound (XVI) is reacted with the compound of the following general formula (XVII), HX-(CH ₂ ) _n -R ⁴ (XVII) wherein R ⁴ represents a protected amino group, n represents an integer of 1-6, and X represents an oxygen atom or a sulfur atom; or (2) in the presence of a phosphine derivative and an azo-compound, compound (XV) is combined with the following general Formula (XVIIa') compound reaction, HO-(CH ₂ ) _n -R ⁴ (XVIIa′) Wherein R ⁴ is as above; or (3) compound (XV) is reacted with the compound of the following general formula (XVIIa") to obtain the isoxazole derivative of the following general formula (XVIII), Ya-(CH ₂ ) _n -R ⁴ (XVIIa″) where ^R4 and n are as above

wherein R ¹ , R ⁴ , m, n, A and X are as described above and the isoxazole derivatives of the following general formula (I) are obtained by removing the amino protecting group of the compound (XVIII), wherein R ¹ , m, n, A and X are as described above, and R ² represents an amino group. 60. The method according to claim 59, Wherein ^R represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a hydroxyl group, a methylthio group, an ethylthio group , amino, methylamino, ethylamino, dimethylamino, formyloxy, acetoxy, methoxycarbonyl, ethoxycarbonyl, carboxyl, carbamoyl, nitro or cyano groups, n is 2, and Ring A represents phenyl, naphthyl and pyridyl rings. 61. The method according to claim 59, wherein ^R represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, a methylthio group, a difluoro-methoxy group, a methoxycarbonyl group, a nitro group or cyano group, R ⁴ represents tert-butoxycarbonylamino, m is 2, n is 2, Ring A represents a phenyl or pyridyl ring, X represents an oxygen atom, and Z represents a fluorine atom or a chlorine atom.